ABSTRACT Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the

failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious

glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival.

SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their

oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of

dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism

and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure,

thereby restoring the myocardium to a healthy molecular and cellular phenotype. KEY POINTS * Sodium–glucose cotransporter 2 (SGLT2) inhibitors have a direct cytoprotective effect on the

failing heart that is mediated by SGLT2-independent actions to increase nutrient-deprivation signalling and autophagic flux, thereby reducing cellular stress, promoting mitochondrial health

and renewal, and decreasing pro-inflammatory signalling and apoptosis. * The failing heart is characterized by upregulation of glucose transporter type 1 (GLUT1) levels, increased glycolysis

and impaired glucose oxidation, which lead to cytosolic accumulation of deleterious glucose intermediates that can activate mechanistic target of rapamycin (mTOR) and suppress

nutrient-deprivation signalling. * The failing heart has increased uptake but decreased oxidation of long-chain fatty acids, which impairs ATP production and leads to cytosolic accumulation

of deleterious lipid intermediates that result from impaired mitochondrial function and nutrient-deprivation signalling; the cytosolic accumulation of amino acids can promote the activation

of mTOR. * SGLT2 inhibitors reverse heart failure-related abnormalities in glucose, long-chain fatty acid and amino acid uptake and metabolism by inhibiting GLUT1 (potentially) and by

promoting nutrient-deprivation signalling and restoring mitochondrial health and renewal, which increases nutrient oxidation and oxidative phosphorylation and reduces the cytosolic

accumulation of deleterious glucose and lipid by-products. * The ketonaemia that accompanies SGLT2 inhibition does not act as an energy substrate for ATP production but might promote

nutrient-deprivation signalling, reduce the activation of pro-inflammatory pathways and increase autophagic flux. * SGLT2 inhibitors might facilitate ATP and haemoglobin production by

increasing the pool of bioreactive cytosolic Fe2+ as a result of the SGLT2 inhibitor-induced decrease in hepcidin and ferritin levels, thereby alleviating the state of inflammation-mediated

functional iron deficiency that is observed in heart failure. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $29.99 / 30 days cancel any time Learn

more Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to

full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our

FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE SGLT2 INHIBITOR EMPAGLIFLOZIN IMPROVES CARDIAC ENERGY STATUS VIA MITOCHONDRIAL ATP PRODUCTION IN DIABETIC MICE

Article Open access 17 March 2023 SGLT2 INHIBITION MITIGATES TRANSITION FROM ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE BY SUPPRESSING FERROPTOSIS Article Open access 02 September 2024

EFFECTS OF EMPAGLIFLOZIN AND DAPAGLIFLOZIN IN ALLEVIATING CARDIAC FIBROSIS THROUGH SIRT6-MEDIATED OXIDATIVE STRESS REDUCTION Article Open access 28 December 2024 REFERENCES * Giugliano, D.

et al. SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs. _Cardiovasc. Diabetol._ 20, 236 (2021). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Mordi, N. A. et al. Renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic

heart failure: the RECEDE-CHF trial. _Circulation_ 142, 1713–1724 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Scholtes, R. A. et al. The adaptive renal response for

volume homeostasis during 2 weeks of dapagliflozin treatment in people with type 2 diabetes and preserved renal function on a sodium-controlled diet. _Kidney Int. Rep._ 7, 1084–1092 (2022).

Article  PubMed  PubMed Central  Google Scholar  * Zannad, F. et al. Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights from the EMPEROR program. _Eur.

Heart J._ 10.1093eurheartj/ehac495 (2022). * Januzzi, J. L. Jr. et al. EMPEROR-reduced trial committees and investigators. Prognostic importance of NT-proBNP and effect of empagliflozin in

the EMPEROR-reduced trial. _J. Am. Coll. Cardiol._ 78, 1321–1332 (2021). Article  CAS  PubMed  Google Scholar  * Nassif, M. E. et al. Empagliflozin effects on pulmonary artery pressure in

patients with heart failure: results from the EMBRACE-HF trial. _Circulation_ 143, 1673–1686 (2021). Article  CAS  PubMed  Google Scholar  * Omar, M. et al. Effect of empagliflozin on blood

volume redistribution in patients with chronic heart failure and reduced ejection fraction: an analysis from the Empire HF randomized clinical trial. _Circ. Heart Fail._ 15, e009156 (2022).

Article  CAS  PubMed  Google Scholar  * Ferrannini, E. et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and

patients with type 2 diabetes. _Diabetes_ 65, 1190–1195 (2016). Article  CAS  PubMed  Google Scholar  * Petrie, M. C. et al. Effect of dapagliflozin on worsening heart failure and

cardiovascular death in patients with heart failure with and without diabetes. _JAMA_ 323, 1353–1368 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sayour, A. A. et al.

Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure. _Cardiovasc. Diabetol._ 19, 159 (2020). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Marfella, R. et al. Sodium-glucose cotransporter-2 (SGLT2) expression in diabetic and non-diabetic failing human cardiomyocytes. _Pharmacol. Res._

184, 106448 (2022). Article  CAS  PubMed  Google Scholar  * Packer, M. Critical reanalysis of the mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors and reaffirmation of the

nutrient deprivation signaling/autophagy hypothesis. _Circulation_ 146, 1383–1405 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Packer, M. Cardioprotective effects of

sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors. _Circ. Heart Fail._ 13, e007197 (2020).

Article  CAS  PubMed  Google Scholar  * Vallon, V. & Nakagawa, T. Renal tubular handling of glucose and fructose in health and disease. _Compr. Physiol._ 12, 2995–3044 (2021). Article 

PubMed  PubMed Central  Google Scholar  * Pessoa, T. D., Campos, L. C., Carraro-Lacroix, L., Girardi, A. C. & Malnic, G. Functional role of glucose metabolism, osmotic stress, and

sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. _J. Am. Soc. Nephrol._ 25, 2028–2039 (2014). Article  CAS  PubMed

  PubMed Central  Google Scholar  * Li, X. et al. Direct cardiac actions of the sodium glucose co-transporter 2 inhibitor empagliflozin improve myocardial oxidative phosphorylation and

attenuate pressure-overload heart failure. _J. Am. Heart Assoc._ 10, e018298 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Borges-Júnior, F. A. et al. Empagliflozin

inhibits proximal tubule NHE3 activity, preserves GFR, and restores euvolemia in nondiabetic rats with induced heart failure. _J. Am. Soc. Nephrol._ 32, 1616–1629 (2021). Article  PubMed 

PubMed Central  Google Scholar  * Baartscheer, A. et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits.

_Diabetologia_ 60, 568–573 (2017). Article  CAS  PubMed  Google Scholar  * Philippaert, K. et al. Cardiac late sodium channel current is a molecular target for the sodium/glucose

cotransporter 2 inhibitor empagliflozin. _Circulation_ 143, 2188–2204 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Mustroph, J. et al. Empagliflozin inhibits cardiac late

sodium current by Ca/calmodulin-dependent kinase II. _Circulation_ 146, 1259–1261 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Vila-Petroff, M. et al.

Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation. _J. Mol. Cell. Cardiol._ 49, 106–112 (2010). Article  CAS

  PubMed  Google Scholar  * Wagner, S. et al. Reactive oxygen species-activated Ca/calmodulin kinase IIδ is required for late I(Na) augmentation leading to cellular Na and Ca overload.

_Circ. Res._ 108, 555–565 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Chung, Y. J. et al. Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin

does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart. _Cardiovasc. Res._ 117, 2794–2806 (2021). Article  CAS  PubMed  Google Scholar  * Baker, H. E. et al. Acute SGLT-2i

treatment improves cardiac efficiency during myocardial ischemia independent of Na+/H+ exchanger-1. _Int. J. Cardiol._ 363, 138–148 (2022). Article  PubMed  Google Scholar  * Moopanar, T. R.

et al. AICAR inhibits the Na+/H+ exchanger in rat hearts–possible contribution to cardioprotection. _Pflug. Arch._ 453, 147–156 (2006). Article  CAS  Google Scholar  * Liao, W., Rao, Z.,

Wu, L., Chen, Y. & Li, C. Cariporide attenuates doxorubicin-induced cardiotoxicity in rats by inhibiting oxidative stress, inflammation and apoptosis partly through regulation of

Akt/GSK-3β and Sirt1 signaling pathway. _Front. Pharmacol._ 13, 850053 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gupta, A. et al. Creatine kinase-mediated improvement

of function in failing mouse hearts provides causal evidence the failing heart is energy starved. _J. Clin. Invest._ 122, 291–302 (2012). Article  CAS  PubMed  Google Scholar  * Gupta, A.

& Houston, B. A comprehensive review of the bioenergetics of fatty acid and glucose metabolism in the healthy and failing heart in nondiabetic condition. _Heart Fail. Rev._ 22, 825–842

(2017). Article  CAS  PubMed  Google Scholar  * Carley, A. N. et al. Short-chain fatty acids outpace ketone oxidation in the failing heart. _Circulation_ 143, 1797–1808 (2021). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Murashige, D. et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. _Science_ 370, 364–368 (2020). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Bedi, K. C. Jr et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human

heart failure. _Circulation_ 133, 706–716 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ferrannini, E., Mark, M. & Mayoux, E. C. V. protection in the EMPA-REG OUTCOME

trial: a “thrifty substrate” hypothesis. _Diabetes Care_ 39, 1108–1114 (2016). Article  PubMed  Google Scholar  * Klip, I. T. et al. Iron deficiency in chronic heart failure: an

international pooled analysis. _Am. Heart J._ 165, 575–582 (2013). Article  CAS  PubMed  Google Scholar  * Hoes, M. F. et al. Iron deficiency impairs contractility of human cardiomyocytes

through decreased mitochondrial function. _Eur. J. Heart Fail._ 20, 910–919 (2018). Article  CAS  PubMed  Google Scholar  * Docherty, K. F. et al. Iron deficiency in heart failure and effect

of dapagliflozin: findings from DAPA-HF. _Circulation_ 146, 980–994 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sharma, S. et al. Intramyocardial lipid accumulation in

the failing human heart resembles the lipotoxic rat heart. _FASEB J._ 18, 1692–1700 (2004). Article  CAS  PubMed  Google Scholar  * Akkafa, F. et al. Reduced SIRT1 expression correlates with

enhanced oxidative stress in compensated and decompensated heart failure. _Redox Biol._ 6, 169–173 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang, B. et al. AMPKα2

protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation. _Circ. Res._ 122, 712–729 (2018). Article  CAS  PubMed  Google Scholar  * Faerber, G. et

al. Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor γ coactivator levels and mitochondrial dysfunction. _J.

Thorac. Cardiovasc. Surg._ 141, 492–500 (2011). Article  CAS  PubMed  Google Scholar  * Castillo, E. C. et al. Mitochondrial hyperacetylation in the failing hearts of obese patients mediated

partly by a reduction in SIRT3: The involvement of the mitochondrial permeability transition pore. _Cell Physiol. Biochem._ 53, 465–479 (2019). Article  CAS  PubMed  Google Scholar  * Yano,

T. et al. Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy. _J. Mol. Cell Cardiol._ 91, 6–9 (2016). Article  CAS  PubMed  Google Scholar  * Zhang, D. et

al. mTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. _J. Clin. Invest._ 120, 2805–2816 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Matsushima, S. & Sadoshima, J. The role of sirtuins in cardiac disease. _Am. J. Physiol. Heart Circ. Physiol._ 309, H1375–H1389 (2015). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Chen, L. et al. PGC-1α-mediated mitochondrial quality control: molecular mechanisms and implications for heart failure. _Front. Cell Dev. Biol._ 10, 871357 (2022). Article  PubMed

  PubMed Central  Google Scholar  * Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. _Nat. Rev. Mol. Cell Biol._ 19, 121–135 (2018). Article  CAS 

PubMed  Google Scholar  * Gao, G. et al. Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. _Int. J. Mol.

Med._ 45, 195–209 (2020). PubMed  Google Scholar  * Tomczyk, M. M. et al. Mitochondrial sirtuin-3 (SIRT3) prevents doxorubicin-induced dilated cardiomyopathy by modulating protein

acetylation and oxidative stress. _Circ. Heart Fail._ 15, e008547 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Li, Y. et al. AMPK inhibits cardiac hypertrophy by promoting

autophagy via mTORC1. _Arch. Biochem. Biophys._ 558, 79–86 (2014). Article  CAS  PubMed  Google Scholar  * Pires Da Silva, J. et al. SIRT1 protects the heart from ER stress-induced injury

by promoting eEF2K/eEF2-dependent autophagy. _Cells_ 9, 426 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang, T., Liu, C. F., Zhang, T. N., Wen, R. & Song, W. L.

Overexpression of peroxisome proliferator-activated receptor γ coactivator 1-α protects cardiomyocytes from lipopolysaccharide-induced mitochondrial damage and apoptosis. _Inflammation_ 43,

1806–1820 (2020). Article  CAS  PubMed  Google Scholar  * Mizushima, N. & Levine, B. Autophagy in human diseases. _N. Engl. J. Med._ 383, 1564–1576 (2020). Article  CAS  PubMed  Google

Scholar  * Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. _Cell_ 176, 11–42 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lin,

B. et al. Sirt1 improves heart failure through modulating the NF-κB p65/microRNA-155/BNDF signaling cascade. _Aging_ 13, 14482–14498 (2020). Article  PubMed  PubMed Central  Google Scholar

  * Han, Y. et al. SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion. _Redox Biol._ 34, 101538 (2020). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Chen, Y., He, T., Zhang, Z. & Zhang, J. Activation of SIRT1 by resveratrol alleviates pressure overload-induced cardiac hypertrophy via suppression of

TGF-β1 signaling. _Pharmacology_ 106, 667–681 (2021). Article  CAS  PubMed  Google Scholar  * Packer, M. Role of deranged energy deprivation signaling in the pathogenesis of cardiac and

renal disease in states of perceived nutrient overabundance. _Circulation_ 141, 2095–2105 (2020). Article  CAS  PubMed  Google Scholar  * Packer, M. SGLT2 inhibitors produce cardiorenal

benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: a paradigm shift in understanding their mechanism of action. _Diabetes Care_ 43, 508–511 (2020).

Article  CAS  PubMed  Google Scholar  * Ying, Y. et al. Phloretin protects against cardiac damage and remodeling via restoring SIRT1 and anti-inflammatory effects in the

streptozotocin-induced diabetic mouse model. _Aging_ 11, 2822–2835 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Koyani, C. N. et al. Empagliflozin protects heart from

inflammation and energy depletion via AMPK activation. _Pharmacol. Res._ 158, 104870 (2020). Article  CAS  PubMed  Google Scholar  * Lu, Q. et al. Empagliflozin attenuates ischemia and

reperfusion injury through LKB1/AMPK signaling pathway. _Mol. Cell Endocrinol._ 501, 110642 (2020). Article  CAS  PubMed  Google Scholar  * Wang, C. Y. et al. TLR9 binding to Beclin 1 and

mitochondrial SIRT3 by a sodium-glucose co-transporter 2 inhibitor protects the heart from doxorubicin toxicity. _Biology_ 9, 369 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Kondo, H. et al. Effects of canagliflozin on human myocardial redox signalling: clinical implications. _Eur. Heart J._ 42, 4947–4960 (2021). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Lee, C. C., Chen, W. T., Chen, S. Y. & Lee, T. M. Dapagliflozin attenuates arrhythmic vulnerabilities by regulating connexin43 expression via the AMPK pathway in

post-infarcted rat hearts. _Biochem. Pharmacol._ 192, 114674 (2021). Article  CAS  PubMed  Google Scholar  * Ren, F. F. et al. Dapagliflozin attenuates pressure overload-induced myocardial

remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress. _Acta Pharmacol. Sin._ 43, 1721–1732 (2022). Article  CAS  PubMed  Google Scholar  * Ren, C. et al.

Sodium-glucose cotransporter-2 inhibitor empagliflozin ameliorates sunitinib-induced cardiac dysfunction via regulation of AMPK-mTOR signaling pathway-mediated autophagy. _Front. Pharmacol._

12, 664181 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sun, P. et al. Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by

inhibiting the mTOR/HIF-1α pathway. _iScience_ 24, 102521 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tian, G. et al. Empagliflozin alleviates ethanol-induced

cardiomyocyte injury through inhibition of mitochondrial apoptosis via a SIRT1/PTEN/Akt pathway. _Clin. Exp. Pharmacol. Physiol._ 48, 837–845 (2021). Article  CAS  PubMed  Google Scholar  *

Yu, Y. W. et al. Sodium-glucose co-transporter-2 inhibitor of dapagliflozin attenuates myocardial ischemia/reperfusion injury by limiting NLRP3 inflammasome activation and modulating

autophagy. _Front. Cardiovasc. Med._ 8, 768214 (2022). Article  PubMed  PubMed Central  Google Scholar  * He, L. et al. An effective sodium-dependent glucose transporter 2 inhibition,

canagliflozin, prevents development of hypertensive heart failure in Dahl salt-sensitive rats. _Front. Pharmacol._ 13, 856386 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Aragón-Herrera, A. et al. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. _Biochem. Pharmacol._ 170,

113677 (2019). Article  PubMed  Google Scholar  * Li, X. et al. Direct cardiac actions of sodium-glucose cotransporter 2 inhibition improve mitochondrial function and attenuate oxidative

stress in pressure overload-induced heart failure. _Front. Cardiovasc. Med._ 9, 859253 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Packer, M. Mutual antagonism of

hypoxia-inducible factor isoforms in cardiac, vascular, and renal disorders. _JACC Basic Transl. Sci._ 5, 961–968 (2020). Article  PubMed  PubMed Central  Google Scholar  * Chen, R. et al.

The acetylase/deacetylase couple CREB-binding protein/sirtuin 1 controls hypoxia-inducible factor 2 signaling. _J. Biol. Chem._ 287, 30800–30811 (2012). Article  CAS  PubMed  PubMed Central

  Google Scholar  * He, X. et al. Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction. _J. Mol. Cell Cardiol._ 112, 104–113 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Yang, Z. et al. SGLT2 inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the HIF-2α signaling pathway

in arrhythmogenic cardiomyopathy. _FASEB J._ 36, e22410 (2022). Article  CAS  PubMed  Google Scholar  * Fitchett, D. et al. Mediators of the improvement in heart failure outcomes with

empagliflozin in the EMPA-REG OUTCOME trial. ESC. _Heart Fail._ 8, 4517–4527 (2021). Google Scholar  * Umino, H. et al. High basolateral glucose increases sodium-glucose cotransporter 2 and

reduces sirtuin-1 in renal tubules through glucose transporter-2 detection. _Sci. Rep._ 8, 6791 (2018). Article  PubMed  PubMed Central  Google Scholar  * Wicik, Z. et al. Characterization

of the SGLT2 interaction network and its regulation by SGLT2 inhibitors: a bioinformatic analysis. _Front. Pharmacol._ 13, 901340 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Lopaschuk, G. D., Karwi, Q. G., Tian, R., Wende, A. R. & Abel, E. D. Cardiac energy metabolism in heart failure. _Circ. Res._ 128, 1487–1513 (2021). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Mohamed, T. M. A., Abouleisa, R. & Hill, B. G. Metabolic determinants of cardiomyocyte proliferation. _Stem Cell_ 40, 458–467 (2022). Article  Google Scholar 

* Shin, A. N. et al. SIRT1 increases cardiomyocyte binucleation in the heart development. _Oncotarget_ 9, 7996–8010 (2018). Article  PubMed  PubMed Central  Google Scholar  * Garbern, J. C.

et al. Inhibition of mTOR signaling enhances maturation of cardiomyocytes derived from human-induced pluripotent stem cells via p53-induced quiescence. _Circulation_ 141, 285–300 (2020).

Article  CAS  PubMed  Google Scholar  * Zhang, P., Shan, T., Liang, X., Deng, C. & Kuang, S. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development

in mice. _Biochem. Biophys. Res. Commun._ 452, 53–59 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sánchez-Díaz, M., Nicolás-Ávila, J. Á., Cordero, M. D. & Hidalgo, A.

Mitochondrial adaptations in the growing heart. _Trends Endocrinol. Metab._ 31, 308–319 (2020). Article  PubMed  Google Scholar  * Lehman, J. J. & Kelly, D. P. Transcriptional activation

of energy metabolic switches in the developing and hypertrophied heart. _Clin. Exp. Pharmacol. Physiol._ 29, 339–345 (2002). Article  CAS  PubMed  Google Scholar  * Gong, G. et al.

Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. _Science_ 350, aad2459 (2015). Article  PubMed  PubMed Central  Google Scholar  * Kantor, P. F., Robertson,

M. A., Coe, J. Y. & Lopaschuk, G. D. Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism. _J. Am. Coll.

Cardiol._ 33, 1724–1734 (1999). Article  CAS  PubMed  Google Scholar  * Bertrand, L. et al. Glucose transporters in cardiovascular system in health and disease. _Pflug. Arch._ 472, 1385–1399

(2020). Article  CAS  Google Scholar  * Heilig, C. W. et al. Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy.

_Proc. Natl Acad. Sci. USA_ 100, 15613–15618 (2003). Article  CAS  PubMed  PubMed Central  Google Scholar  * Nisr, R. B. & Affouritit, C. Insulin acutely improves mitochondrial function

of rat and human skeletal muscle by increasing coupling efficiency of oxidative phosphorylation. _Biochim. Biophys. Acta_ 1837, 270–276 (2014). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Kato, T. et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. _Circ. Heart Fail._ 3, 420–430 (2010). Article  PubMed  Google

Scholar  * Pereira, R. O. et al. Inducible overexpression of GLUT1 prevents mitochondrial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left

ventricular dysfunction. _J. Am. Heart Assoc._ 2, e000301 (2013). Article  PubMed  PubMed Central  Google Scholar  * Fillmore, N. et al. Uncoupling of glycolysis from glucose oxidation

accompanies the development of heart failure with preserved ejection fraction. _Mol. Med._ 24, 3 (2018). Article  PubMed  PubMed Central  Google Scholar  * Zhabyeyev, P. et al.

Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. _Cardiovasc. Res._ 97, 676–685 (2013). Article  CAS  PubMed  Google

Scholar  * Kutsche, H. S. et al. Alterations in glucose metabolism during the transition to heart failure: the contribution of UCP-2. _Cells_ 9, 552 (2020). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Diakos, N. A. et al. Evidence of glycolysis up‐regulation and pyruvate mitochondrial oxidation mismatch during mechanical unloading of the failing human heart:

implications for cardiac reloading and conditioning. _JACC Basic Transl. Sci._ 1, 432–444 (2016). Article  PubMed  PubMed Central  Google Scholar  * Bhaskar, P. T. et al. mTORC1

hyperactivity inhibits serum deprivation-induced apoptosis via increased hexokinase II and GLUT1 expression, sustained Mcl-1 expression, and glycogen synthase kinase 3beta inhibition. _Mol.

Cell Biol._ 29, 5136–5147 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sokolovska, J. et al. Influence of metformin on GLUT1 gene and protein expression in rat

streptozotocin diabetes mellitus model. _Arch. Physiol. Biochem._ 116, 137–145 (2010). Article  CAS  PubMed  Google Scholar  * Hölscher, M. et al. Unfavourable consequences of chronic

cardiac HIF-1α stabilization. _Cardiovasc. Res._ 94, 77–86 (2012). Article  PubMed  Google Scholar  * Yang, J. & Holman, G. D. Long-term metformin treatment stimulates cardiomyocyte

glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis. _Endocrinology_ 147, 2728–2736 (2006). Article  CAS  PubMed  Google Scholar  * Li, X. et

al. Enhancement of glucose metabolism via PGC-1α participates in the cardioprotection of chronic intermittent hypobaric hypoxia. _Front. Physiol._ 7, 219 (2016). Article  PubMed  PubMed

Central  Google Scholar  * Murugasamy, K., Munjal, A. & Sundaresan, N. R. Emerging roles of SIRT3 in cardiac metabolism. _Front. Cardiovasc. Med._ 9, 850340 (2022). Article  CAS  PubMed

  PubMed Central  Google Scholar  * Bersin, R. M. et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. _J. Am. Coll.

Cardiol._ 23, 1617–1624 (1994). Article  CAS  PubMed  Google Scholar  * Clanachan, A. S. Contribution of protons to post-ischemic Na+ and Ca2+ overload and left ventricular mechanical

dysfunction. _J. Cardiovasc. Electrophysiol._ 17, S141–S148 (2006). Article  PubMed  Google Scholar  * Chen, Z. T. et al. Glycolysis inhibition alleviates cardiac fibrosis after myocardial

infarction by suppressing cardiac fibroblast activation. _Front. Cardiovasc. Med._ 8, 701745 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zheng, Z. et al. Enhanced

glycolytic metabolism contributes to cardiac dysfunction in polymicrobial sepsis. _J. Infect. Dis._ 215, 1396–1406 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sen, S. et

al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. _J. Am. Heart Assoc._ 2, e004796 (2013). Article  PubMed  PubMed Central  Google Scholar  * Roberts,

D. J. & Miyamoto, S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. _Cell Death Differ._ 22, 248–257 (2015). Article

  CAS  PubMed  Google Scholar  * Tran, D. H. et al. Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling. _Nat. Commun._ 11, 1771 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Marsh, S. A., Powell, P. C., Dell’italia, L. J. & Chatham, J. C. Cardiac O-GlcNAcylation blunts autophagic signaling in the

diabetic heart. _Life Sci._ 92, 648–656 (2013). Article  CAS  PubMed  Google Scholar  * Gelinas, R. et al. AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation. _Nat.

Commun._ 9, 374 (2018). Article  PubMed  PubMed Central  Google Scholar  * Chai, Q. et al. Knockdown of SGLT1 prevents the apoptosis of cardiomyocytes induced by glucose fluctuation via

relieving oxidative stress and mitochondrial dysfunction. _Biochem. Cell Biol._ 99, 356–363 (2021). Article  CAS  PubMed  Google Scholar  * Ferté, L. et al. New insight in understanding the

contribution of SGLT1 in cardiac glucose uptake: evidence for a truncated form in mice and humans. _Am. J. Physiol. Heart Circ. Physiol._ 320, H838–H853 (2021). Article  PubMed  PubMed

Central  Google Scholar  * Bhatt, D. L. et al. SOLOIST-WHF trial investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure. _N. Engl. J. Med._ 384, 117–128

(2021). Article  CAS  PubMed  Google Scholar  * Santos-Gallego, C. G. et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing

myocardial energetics. _J. Am. Coll. Cardiol._ 73, 1931–1944 (2019). Article  CAS  PubMed  Google Scholar  * Lauritsen, K. M. et al. SGLT2 inhibition does not affect myocardial fatty acid

oxidation or uptake, but reduces myocardial glucose uptake and blood flow in individuals with type 2 diabetes: a randomized double-blind, placebo-controlled crossover trial. _Diabetes_ 70,

800–808 (2021). Article  CAS  PubMed  Google Scholar  * Asrih, M., Lerch, R., Papageorgiou, I., Pellieux, C. & Montessuit, C. Differential regulation of stimulated glucose transport by

free fatty acids and PPARα or -δ agonists in cardiac myocytes. _Am. J. Physiol. Endocrinol. Metab._ 302, E872–E884 (2012). Article  CAS  PubMed  Google Scholar  * Yurista, S. R. et al.

Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. _Eur. J. Heart

Fail._ 21, 862–873 (2019). Article  CAS  PubMed  Google Scholar  * Zhang, H. et al. Empagliflozin decreases lactate generation in an NHE-1 dependent fashion and increases α-ketoglutarate

synthesis from palmitate in type ii diabetic mouse hearts. _Front. Cardiovasc. Med._ 7, 592233 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Verma, S. et al. Empagliflozin

increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. _JACC Basic Transl. Sci._ 3, 575–587 (2018). Article 

PubMed  PubMed Central  Google Scholar  * Xie, B. et al. Empagliflozin restores cardiac metabolic flexibility in diet-induced obese C57BL6/J mice. _Curr. Res. Physiol._ 5, 232–239 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Uthman, L. et al. Novel anti-inflammatory effects of canagliflozin involving hexokinase II in lipopolysaccharide-stimulated human

coronary artery endothelial cells. _Cardiovasc. Drugs Ther._ 35, 1083–1094 (2021). Article  CAS  PubMed  Google Scholar  * Joubert, M. et al. The sodium-glucose cotransporter 2 inhibitor

dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. _Diabetes_ 66, 1030–1040 (2017). Article  CAS  PubMed  Google Scholar  * Ducheix, S., Magré, J., Cariou, B.

& Prieur, X. Chronic O-GlcNAcylation and diabetic cardiomyopathy: the bitterness of glucose. _Front. Endocrinol._ 9, 642 (2018). Article  Google Scholar  * Hawley, S. A. et al. The

Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. _Diabetes_ 65, 2784–2794 (2016). Article  CAS 

PubMed  Google Scholar  * Karlstaedt, A., Khanna, R., Thangam, M. & Taegtmeyer, H. Glucose 6-phosphate accumulates via phosphoglucose isomerase inhibition in heart muscle. _Circ. Res._

126, 60–74 (2020). Article  CAS  PubMed  Google Scholar  * Davogustto, G. E. et al. Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy. _Mol. Cell Cardiol._ 158, 115–127

(2021). Article  CAS  Google Scholar  * Roberts, D. J., Tan-Sah, V. P., Ding, E. Y., Smith, J. M. & Miyamoto, S. Hexokinase-II positively regulates glucose starvation-induced autophagy

through TORC1 inhibition. _Mol. Cell_ 53, 521–533 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Brainard, R. E. & Facundo, H. T. Cardiac hypertrophy drives PGC-1α

suppression associated with enhanced O-glycosylation. _Biochim. Biophys. Acta Mol. Basis Dis._ 1867, 166080 (2021). Article  CAS  PubMed  Google Scholar  * Bullen, J. W. et al. Cross-talk

between two essential nutrient-sensitive enzymes: O-GlcNAc transferase (OGT) and AMP-activated protein kinase (AMPK). _J. Biol. Chem._ 289, 10592–10606 (2014). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Luiken, J. J. F. P., Nabben, M., Neumann, D. & Glatz, J. F. C. Understanding the distinct subcellular trafficking of CD36 and GLUT4 during the development of

myocardial insulin resistance. _Biochim. Biophys. Acta Mol. Basis Dis._ 1866, 165775 (2020). Article  CAS  PubMed  Google Scholar  * van der Vusse, G. J., van Bilsen, M., Glatz, J. F.,

Hasselbaink, D. M. & Luiken, J. J. Critical steps in cellular fatty acid uptake and utilization. _Mol. Cell Biochem._ 239, 9–15 (2002). Article  PubMed  Google Scholar  * Sorokina, N. et

al. Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied

hearts. _Circulation_ 115, 2033–2041 (2007). Article  CAS  PubMed  Google Scholar  * Warren, J. S. et al. Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart.

_Proc. Natl Acad. Sci. USA_ 115, E7871–E7880 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fukushima, A. & Lopaschuk, G. D. Cardiac fatty acid oxidation in heart

failure associated with obesity and diabetes. _Biochim. Biophys. Acta_ 1861, 1525–1534 (2016). Article  CAS  PubMed  Google Scholar  * Osorio, J. C. et al. Impaired myocardial fatty acid

oxidation and reduced protein expression of retinoid x receptor-alpha in pacing-induced heart failure. _Circulation_ 106, 606–612 (2002). Article  CAS  PubMed  Google Scholar  * Doenst, T.

et al. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. _Cardiovasc. Res._ 86, 461–470 (2010).

Article  CAS  PubMed  Google Scholar  * Choi, Y. S. et al. Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion. _J.

Mol. Cell Cardiol._ 100, 64–71 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Law, B. A. et al. Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction,

oxidative stress, and cell death in cardiomyocytes. _FASEB J._ 32, 1403–1416 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hunter, W. G. et al. Metabolomic profiling

identifies novel circulating biomarkers of mitochondrial dysfunction differentially elevated in heart failure with preserved versus reduced ejection fraction: evidence for shared metabolic

impairments in clinical heart failure. _J. Am. Heart Assoc._ 5, e003190 (2016). Article  PubMed  PubMed Central  Google Scholar  * Gupte, A. A. et al. Mechanical unloading promotes

myocardial energy recovery in human heart failure. _Circ. Cardiovasc. Genet._ 7, 266–276 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Previs, M. J. et al. Defects in the

proteome and metabolome in human hypertrophic cardiomyopathy. _Circ. Heart Fail._ 15, e009521 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Dávila-Román, V. G. et al.

Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. _J. Am. Coll. Cardiol._ 40, 271–277 (2002). Article  PubMed  Google Scholar  * Yan, J. et al.

Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity. _Circulation_ 119, 2818–2828 (2009). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Heather, L. C. et al. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart.

_Cardiovasc. Res._ 72, 430–437 (2006). Article  CAS  PubMed  Google Scholar  * Sihag, S., Cresci, S., Li, A. Y., Sucharov, C. C. & Lehman, J. J. PGC-1alpha and ERRalpha target gene

downregulation is a signature of the failing human heart. _J. Mol. Cell Cardiol._ 46, 201–212 (2009). Article  CAS  PubMed  Google Scholar  * Knuuti, J. & Opie, L. H. The

adrenergic-fatty acid load in heart failure. _J. Am. Coll. Cardiol._ 54, 1637–1646 (2009). Article  PubMed  Google Scholar  * Pohl, J. et al. Fatty acid transporters in plasma membranes of

cardiomyocytes in patients with dilated cardiomyopathy. _Eur. J. Med. Res._ 5, 438–442 (2000). CAS  PubMed  Google Scholar  * Goldberg, I. J., Trent, C. M. & Schulze, C. Lipid metabolism

and toxicity in the heart. _Cell Metab._ 15, 805–812 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wu, Y., Song, P., Xu, J., Zhang, M. & Zou, M. H. Activation of

protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. _J. Biol. Chem._ 282, 9777–9788 (2007). Article  CAS  PubMed  Google Scholar  * Smolka, C. et al.

Cardiomyocyte-specific miR-100 overexpression preserves heart function under pressure overload in mice and diminishes fatty acid uptake as well as ROS production by direct suppression of

Nox4 and CD36. _FASEB J._ 35, e21956 (2021). Article  CAS  PubMed  Google Scholar  * He, L. et al. Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac

hypertrophy caused by lipotoxicity. _Circulation_ 126, 1705–1716 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kolwicz, S. C. Jr. et al. Cardiac-specific deletion of acetyl

CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. _Circ. Res._ 111, 728–738 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shao, D. et

al. Increasing fatty acid oxidation prevents high-fat diet-induced cardiomyopathy through regulating Parkin-mediated mitophagy. _Circulation_ 142, 983–997 (2020). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Huang, W. P. et al. Fenofibrate attenuates doxorubicin-induced cardiac dysfunction in mice via activating the eNOS/EPC pathway. _Sci. Rep._ 11, 1159 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Brigadeau, F. et al. The PPARalpha activator fenofibrate slows down the progression of the left ventricular dysfunction in porcine

tachycardia-induced cardiomyopathy. _J. Cardiovasc. Pharmacol._ 49, 408–415 (2007). Article  CAS  PubMed  Google Scholar  * Zhang, J. et al. Fenofibrate increases cardiac autophagy via

FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of type 1 diabetic mice. _Clin. Sci._ 130, 625–641 (2016). Article  CAS  Google Scholar  * Ferreira, J. P. et al. Fenofibrate

and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. _Diabetes Care_ 45, 1584–1591 (2022). Article  CAS  PubMed  Google Scholar  * Supruniuk, E., Mikłosz, A.

& Chabowski, A. The implication of PGC-1α on fatty acid transport across plasma and mitochondrial membranes in the insulin sensitive tissues. _Front. Physiol._ 8, 923 (2017). Article 

PubMed  PubMed Central  Google Scholar  * Wang, S. Y. et al. Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development

of diabetic cardiomyopathy. _J. Mol. Med._ 98, 245–261 (2020). Article  CAS  PubMed  Google Scholar  * Hirschey, M. D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible

enzyme deacetylation. _Nature_ 464, 121–125 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wen, D. T. et al. Endurance exercise resistance to lipotoxic cardiomyopathy is

associated with cardiac NAD+/dSIR2/PGC-1α pathway activation in old _Drosophila_. _Biol. Open._ 8, bio044719 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Chen, T. et al.

Mouse SIRT3 attenuates hypertrophy-related lipid accumulation in the heart through the deacetylation of LCAD. _PLoS One_ 10, e0118909 (2015). Article  PubMed  PubMed Central  Google Scholar

  * Turdi, S. et al. Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction. _J. Mol. Cell Cardiol._ 50, 712–722 (2011).

Article  CAS  PubMed  Google Scholar  * Sambandam, N. et al. Malonyl-CoA decarboxylase (MCD) is differentially regulated in subcellular compartments by 5’AMP-activated protein kinase

(AMPK). Studies using H9c2 cells overexpressing MCD and AMPK by adenoviral gene transfer technique. _Eur. J. Biochem._ 271, 2831–2840 (2004). Article  CAS  PubMed  Google Scholar  * Bai, F.

et al. Metformin regulates lipid metabolism in a canine model of atrial fibrillation through AMPK/PPAR-α/VLCAD pathway. _Lipids Health Dis._ 18, 109 (2019). Article  PubMed  PubMed Central 

Google Scholar  * Viglino, C., Foglia, B. & Montessuit, C. Chronic AICAR treatment prevents metabolic changes in cardiomyocytes exposed to free fatty acids. _Pflug. Arch._ 471, 1219–1234

(2019). Article  CAS  Google Scholar  * Adrian, L. et al. AMPK prevents palmitic acid-induced apoptosis and lipid accumulation in cardiomyocytes. _Lipids_ 52, 737–750 (2017). Article  CAS 

PubMed  Google Scholar  * Pettersen, I. K. N. et al. Upregulated PDK4 expression is a sensitive marker of increased fatty acid oxidation. _Mitochondrion_ 49, 97–110 (2019). Article  CAS 

PubMed  Google Scholar  * Zhu, Y. et al. Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α. _Am. J. Physiol. Heart Circ. Physiol._

305, H41–H51 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Moellmann, J. et al. The sodium-glucose co-transporter-2 inhibitor ertugliflozin modifies the signature of

cardiac substrate metabolism and reduces cardiac mTOR signalling, endoplasmic reticulum stress and apoptosis. _Diabetes Obes. Metab._ 24, 2263–2272 (2022). Article  CAS  PubMed  Google

Scholar  * Wei, D. et al. Canagliflozin ameliorates obesity by improving mitochondrial function and fatty acid oxidation via PPARα in vivo and in vitro. _Life Sci._ 247, 117414 (2020).

Article  CAS  PubMed  Google Scholar  * Ferrannini, E. et al. Mechanisms of sodium-glucose cotransporter 2 inhibition: insights from large-scale proteomics. _Diabetes Care_ 43, 2183–2189

(2020). Article  CAS  PubMed  Google Scholar  * Furuhashi, M. et al. Possible increase in serum FABP4 level despite adiposity reduction by canagliflozin, an SGLT2 inhibitor. _PLoS ONE_ 11,

e0154482 (2016). Article  PubMed  PubMed Central  Google Scholar  * Grevengoed, T. J., Cooper, D. E., Young, P. A., Ellis, J. M. & Coleman, R. A. Loss of long-chain acyl-CoA synthetase

isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation. _FASEB J._ 29, 4641–4653 (2015). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Crozier, S. J., Bolster, D. R., Reiter, A. K., Kimball, S. R. & Jefferson, L. S. Beta -oxidation of free fatty acids is required to maintain translational

control of protein synthesis in heart. _Am. J. Physiol. Endocrinol. Metab._ 283, E1144–E1150 (2002). Article  CAS  PubMed  Google Scholar  * Essop, M. F. et al. Reduced heart size and

increased myocardial fuel substrate oxidation in ACC2 mutant mice. _Am. J. Physiol. Heart Circ. Physiol._ 295, H256–H265 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Xiao,

X. et al. Peroxisome proliferator-activated receptors gamma and alpha agonists stimulate cardiac glucose uptake via activation of AMP-activated protein kinase. _J. Nutr. Biochem._ 21,

621–626 (2010). Article  PubMed  Google Scholar  * Liu, G. Z. et al. Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR-α/sirtuin 1/PGC-1α pathway. _Br. J.

Pharmacol._ 173, 1095–1109 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Witham, W. G., Yester, K. A. & McGaffin, K. R. A high leucine diet mitigates cardiac injury

and improves survival after acute myocardial infarction. _Metabolism_ 62, 290–302 (2013). Article  CAS  PubMed  Google Scholar  * Kaye, D. M., Parnell, M. M. & Ahlers, B. A. Reduced

myocardial and systemic L-arginine uptake in heart failure. _Circ. Res._ 91, 1198–1203 (2002). Article  CAS  PubMed  Google Scholar  * Kimura, Y. et al. Usefulness of plasma branched-chain

amino acid analysis in predicting outcomes of patients with nonischemic dilated cardiomyopathy. _Int. Heart J._ 61, 739–747 (2020). Article  CAS  PubMed  Google Scholar  * Sansbury, B. E. et

al. Metabolomic analysis of pressure-overloaded and infarcted mouse hearts. _Circ. Heart Fail._ 7, 634–642 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Uddin, G. M. et

al. Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure. _Cardiovasc. Diabetol._ 18, 86 (2019). Article  PubMed  PubMed Central  Google

Scholar  * Sun, H. et al. Catabolic defect of branched-chain amino acids promotes heart failure. _Circulation_ 133, 2038–2049 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Caragnano, A. et al. Autophagy and inflammasome activation in dilated cardiomyopathy. _J. Clin. Med._ 8, 1519 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shao, D. et al.

Glucose promotes cell growth by suppressing branched-chain amino acid degradation. _Nat. Commun._ 9, 2935 (2018). Article  PubMed  PubMed Central  Google Scholar  * Wang, W. et al. Defective

branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. _Am. J. Physiol. Heart Circ. Physiol._ 311, H1160–H1169 (2016).

Article  PubMed  Google Scholar  * Renguet, E. et al. Metabolism and acetylation contribute to leucine-mediated inhibition of cardiac glucose uptake. _Am. J. Physiol. Heart Circ. Physiol._

313, H432–H445 (2017). Article  PubMed  Google Scholar  * Gong, Q. et al. SGLT2 inhibitor-empagliflozin treatment ameliorates diabetic retinopathy manifestations and exerts protective

effects associated with augmenting branched chain amino acids catabolism and transportation in db/db mice. _Biomed. Pharmacother._ 152, 113222 (2022). Article  CAS  PubMed  Google Scholar  *

Kappel, B. A. et al. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. _Circulation_ 136, 969–972 (2017). Article  CAS

  PubMed  Google Scholar  * Palm, C. L., Nijholt, K. T., Bakker, B. M. & Westenbrink, B. D. Short-chain fatty acids in the metabolism of heart failure - rethinking the fat stigma.

_Front. Cardiovasc. Med._ 9, 915102 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sun, W. et al. Alterations of the gut microbiota in patients with severe chronic heart

failure. _Front. Microbiol._ 12, 813289 (2022). Article  PubMed  PubMed Central  Google Scholar  * Jóhannsson, E. et al. Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat

model of congestive heart failure. _Circulation_ 104, 729–734 (2001). Article  PubMed  Google Scholar  * Zhang, L. et al. Sodium butyrate attenuates angiotensin II-induced cardiac

hypertrophy by inhibiting COX2/PGE2 pathway via a HDAC5/HDAC6-dependent mechanism. _J. Cell Mol. Med._ 23, 8139–8150 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hallows,

W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. _Proc. Natl Acad. Sci. USA_ 103, 10230–10235 (2006). Article  CAS  PubMed  PubMed Central

  Google Scholar  * Zhu, Y., Wu, J. & Yuan, S. Y. MCT1 and MCT4 expression during myocardial ischemic-reperfusion injury in the isolated rat heart. _Cell Physiol. Biochem._ 32, 663–674

(2013). Article  CAS  PubMed  Google Scholar  * Zeng, Z. et al. Effects of short-chain acyl-CoA dehydrogenase on cardiomyocyte apoptosis. _J. Cell Mol. Med._ 20, 1381–1391 (2016). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Saucedo-Orozco, H., Voorrips, S. N., Yurista, S. R., de Boer, R. A. & Westenbrink, B. D. SGLT2 inhibitors and ketone metabolism in heart

failure. _J. Lipid Atheroscler._ 11, 1–19 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lommi, J. et al. Blood ketone bodies in congestive heart failure. _J. Am. Coll.

Cardiol._ 28, 665–672 (1996). Article  CAS  PubMed  Google Scholar  * Nagao, M. et al. β-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes.

_Biochem. Biophys. Res. Commun._ 475, 322–328 (2016). Article  CAS  PubMed  Google Scholar  * Nielsen, R. et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in

chronic heart failure patients. _Circulation_ 139, 2129–2141 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yurista, S. R. et al. Ketone ester treatment improves cardiac

function and reduces pathologic remodeling in preclinical models of heart failure. _Circ. Heart Fail._ 14, e007684 (2021). Article  CAS  PubMed  Google Scholar  * Horton, J. L. et al. The

failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. _JCI Insight_ 4, e124079 (2019). Article  PubMed  PubMed Central  Google Scholar  * Ho, K. L. et al. Increased ketone

body oxidation provides additional energy for the failing heart without improving cardiac efficiency. _Cardiovasc. Res._ 115, 1606–1616 (2019). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Uchihashi, M. et al. Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and cardiac remodeling in pressure overload-induced heart failure. _Circ. Heart Fail._ 10,

e004417 (2017). Article  CAS  PubMed  Google Scholar  * Byrne, N. J. et al. Chronically elevating circulating ketones can reduce cardiac inflammation and blunt the development of heart

failure. _Circ. Heart Fail._ 13, e006573 (2020). Article  CAS  PubMed  Google Scholar  * Deng, Y. et al. Targeting mitochondria-inflammation circuit by β-hydroxybutyrate mitigates HFpEF.

_Circ. Res._ 128, 232–245 (2021). Article  CAS  PubMed  Google Scholar  * Liu, Y. et al. Cardioprotective roles of β-hydroxybutyrate against doxorubicin induced cardiotoxicity. _Front.

Pharmacol._ 11, 603596 (2021). Article  PubMed  PubMed Central  Google Scholar  * Nakamura, M. et al. Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and

heart failure. _Cardiovasc. Res._ 117, 2365–2376 (2021). Article  CAS  PubMed  Google Scholar  * Oka, S. I. et al. β-Hydroxybutyrate, a ketone body, potentiates the antioxidant defense via

thioredoxin 1 upregulation in cardiomyocytes. _Antioxid_ 10, 1153 (2021). Article  CAS  Google Scholar  * Kawakami, R. et al. Ketone body and FGF21 coordinately regulate fasting-induced

oxidative stress response in the heart. _Sci. Rep._ 12, 7338 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Xu, M. et al. Choline ameliorates cardiac hypertrophy by

regulating metabolic remodelling and UPRmt through SIRT3-AMPK pathway. _Cardiovasc. Res._ 115, 530–545 (2019). Article  CAS  PubMed  Google Scholar  * Thai, P. N. et al. Ketone ester

D-β-hydroxybutyrate-(R)-1,3 butanediol prevents decline in cardiac function in type 2 diabetic mice. _J. Am. Heart Assoc._ 10, e020729 (2021). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Nilsson, M. I. et al. Nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants enhances autophagic clearance in Pompe disease. _Mol. Genet Metab._ 137, 228–240

(2022). Article  CAS  PubMed  Google Scholar  * Wallenius, K. et al. The SGLT2 inhibitor dapagliflozin promotes systemic FFA mobilization, enhances hepatic β-oxidation, and induces ketosis.

_J. Lipid Res._ 63, 100176 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wolf, P. et al. Gluconeogenesis, but not glycogenolysis, contributes to the increase in endogenous

glucose production by SGLT-2 inhibition. _Diabetes Care_ 44, 541–548 (2021). Article  CAS  PubMed  Google Scholar  * Yang, X. et al. The diabetes medication canagliflozin promotes

mitochondrial remodelling of adipocyte via the AMPK-Sirt1-Pgc-1α signalling pathway. _Adipocyte_ 9, 484–494 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Swe, M. T. et al.

Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats. _Clin. Sci._ 133,

2415–2430 (2019). Article  CAS  Google Scholar  * Erion, D. M. et al. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in

diabetic rats. _Proc. Natl Acad. Sci. USA_ 106, 11288–11293 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hirschey, M. D., Shimazu, T., Capra, J. A., Pollard, K. S. &

Verdin, E. SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. _Aging_ 3, 635–642 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Velasco, G., Geelen,

M. J. H. & Guzmán, M. Control of hepatic fatty acid oxidation by 5′-AMP-activated protein kinase involves a malonyl-CoA-dependent and a malonyl-CoA-independent mechanism. _Arch. Biochem.

Biophys._ 337, 169–175 (1997). Article  CAS  PubMed  Google Scholar  * Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis

and its modulation by ageing. _Nature_ 468, 1100–1104 (2010). Article  CAS  PubMed  Google Scholar  * McCarthy, C. G. et al. Ketone body β-hydroxybutyrate is an autophagy-dependent

vasodilator. _JCI Insight_ 6, e149037 (2021). Article  PubMed  PubMed Central  Google Scholar  * Ferrannini, E. et al. Renal handling of ketones in response to sodium-glucose cotransporter 2

inhibition in patients with type 2 diabetes. _Diabetes Care_ 40, 771–776 (2017). Article  CAS  PubMed  Google Scholar  * Heerspink, H. J. L. et al. DAPA-CKD trial committees and

investigators. Dapagliflozin in patients with chronic kidney disease. _N. Engl. J. Med._ 383, 1436–1446 (2020). Article  CAS  PubMed  Google Scholar  * Sahasrabudhe, V. et al. The effect of

renal impairment on the pharmacokinetics and pharmacodynamics of ertugliflozin in subjects with type 2 diabetes mellitus. _J. Clin. Pharmacol._ 57, 1432–1443 (2017). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Pietschner, R. et al. Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure. _Cardiovasc. Diabetol._ 20, 219 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Selvaraj, S. et al. Metabolomic profiling of the effects of dapagliflozin in heart failure with reduced ejection fraction: DEFINE-HF.

_Circulation_ 146, 808–818 (2022). Article  CAS  PubMed  Google Scholar  * Marilly, E. et al. SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular

outcome trials balancing their risks and benefits. _Diabetologia_ 65, 2000–2010 (2022). Article  CAS  PubMed  Google Scholar  * Packer, M. et al. EMPEROR-reduced trial investigators.

Cardiovascular and renal outcomes with empagliflozin in heart failure. _N. Engl. J. Med._ 383, 1413–1424 (2020). Article  CAS  PubMed  Google Scholar  * Oh, C. M. et al. Cardioprotective

potential of an SGLT2 inhibitor against doxorubicin-induced heart failure. _Korean Circ. J._ 49, 1183–1195 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Byrne, N. J. et al.

Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. _JACC Basic Transl. Sci._ 2, 347–354 (2017). Article  PubMed 

PubMed Central  Google Scholar  * Abdurrachim, D. et al. Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: a

hyperpolarized 13C magnetic resonance spectroscopy study. _Diabetes Obes. Metab._ 21, 357–365 (2019). Article  CAS  PubMed  Google Scholar  * Kimura, T. et al. Inhibitory effects of

tofogliflozin on cardiac hypertrophy in Dahl salt-sensitive and salt-resistant rats fed a high-fat diet. _Int. Heart J._ 60, 728–735 (2019). Article  CAS  PubMed  Google Scholar  * Gaborit,

B. et al. Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study. _Cardiovasc. Diabetol._ 20, 57 (2021). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Tomita, I. et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. _Cell Metab._ 32,

404–419.e6 (2020). Article  CAS  PubMed  Google Scholar  * Papalia, F. et al. Cardiac energetics in patients with chronic heart failure and iron deficiency: an in-vivo 31P magnetic resonance

spectroscopy study. _Eur. J. Heart Fail._ 24, 716–723 (2022). Article  CAS  PubMed  Google Scholar  * Charles-Edwards, G. et al. Effect of iron isomaltoside on skeletal muscle energetics in

patients with chronic heart failure and iron deficiency. _Circulation_ 139, 2386–2398 (2019). Article  CAS  PubMed  Google Scholar  * Haddad, S. et al. Iron-regulatory proteins secure iron

availability in cardiomyocytes to prevent heart failure. _Eur. Heart J._ 38, 362–372 (2017). CAS  PubMed  Google Scholar  * Long, M. et al. DGAT1 activity synchronises with mitophagy to

protect cells from metabolic rewiring by iron depletion. _EMBO J._ 41, e109390 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Jang, S. et al. Elucidating the contribution of

mitochondrial glutathione to ferroptosis in cardiomyocytes. _Redox Biol._ 45, 102021 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tadokoro, T. et al.

Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. _JCI Insight_ 5, e132747 (2020). Article  PubMed  PubMed Central  Google Scholar  * Fang, X. et al.

Ferroptosis as a target for protection against cardiomyopathy. _Proc. Natl Acad. Sci. USA_ 116, 2672–2680 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Komai, K., Kawasaki,

N. K., Higa, J. K. & Matsui, T. The role of ferroptosis in adverse left ventricular remodeling following acute myocardial infarction. _Cells_ 11, 1399 (2022). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Fang, X. et al. Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis. _Circ. Res._ 127, 486–501 (2020). Article  CAS 

PubMed  Google Scholar  * Nemeth, E. & Ganz, T. The role of hepcidin in iron metabolism. _Acta Haematol._ 122, 78–86 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Kralova, B. et al. Developmental changes in iron metabolism and erythropoiesis in mice with human gain-of-function erythropoietin receptor. _Am. J. Hematol._ 97, 1286–1299 (2022). Article 

CAS  PubMed  Google Scholar  * Fang, X., Ardehali, H., Min, J. & Wang, F. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. _Nat. Rev. Cardiol._

https://doi.org/10.1038/s41569-022-00735-4 (2022). Article  PubMed  PubMed Central  Google Scholar  * Ito, J. et al. Iron derived from autophagy-mediated ferritin degradation induces

cardiomyocyte death and heart failure in mice. _eLife_ 10, e62174 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Martínez-Ruiz, A. et al. Soluble TNFα receptor type I and

hepcidin as determinants of development of anemia in the long-term follow-up of heart failure patients. _Clin. Biochem._ 45, 1455–1458 (2012). Article  PubMed  Google Scholar  * Masini, G.

et al. Criteria for iron deficiency in patients with heart failure. _J. Am. Coll. Cardiol._ 79, 341–351 (2022). Article  CAS  PubMed  Google Scholar  * Ghanim, H. et al. Dapagliflozin

suppresses hepcidin and increases erythropoiesis. _J. Clin. Endocrinol. Metab._ 105, dgaa057 (2020). Article  PubMed  Google Scholar  * Thiele, K. et al. Effects of empagliflozin on

erythropoiesis in patients with type 2 diabetes: data from a randomized, placebo-controlled study. _Diabetes Obes. Metab._ 23, 2814–2818 (2021). Article  CAS  PubMed  Google Scholar  * Xin,

H. et al. Hydrogen sulfide attenuates inflammatory hepcidin by reducing IL-6 secretion and promoting SIRT1-mediated STAT3 deacetylation. _Antioxid. Redox Signal._ 24, 70–83 (2016). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Salazar, G. et al. SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence. _Autophagy_ 16, 1092–1110 (2020).

Article  CAS  PubMed  Google Scholar  * Crane, F. L., Navas, P., Low, H., Sun, I. L. & de Cabo, R. Sirtuin activation: a role for plasma membrane in the cell growth puzzle. _J. Gerontol.

A Biol. Sci. Med. Sci._ 68, 368–370 (2013). Article  CAS  PubMed  Google Scholar  * Xu, W. et al. Lethal cardiomyopathy in mice lacking transferrin receptor in the heart. _Cell Rep._ 13,

533–545 (2015). Article  PubMed  PubMed Central  Google Scholar  * Lin, J. et al. Mitochondrial dynamics and mitophagy in cardiometabolic disease. _Front. Cardiovasc. Med._ 9, 917135 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Cui, L. et al. Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction

and toxicity. _Toxicol. Lett._ 275, 28–38 (2017). Article  CAS  PubMed  Google Scholar  * Li, X. et al. NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores

after blood loss. _Blood_ 136, 2691–2702 (2020). PubMed  PubMed Central  Google Scholar  * Berezovsky, B. et al. Effect of erythropoietin on the expression of murine transferrin receptor 2.

_Int. J. Mol. Sci._ 22, 8209 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Honda, H. et al. Associations among erythroferrone and biomarkers of erythropoiesis and iron

metabolism, and treatment with long-term erythropoiesis-stimulating agents in patients on hemodialysis. _PLoS ONE_ 11, e0151601 (2016). Article  PubMed  PubMed Central  Google Scholar  *

Waldman, M. et al. The role of heme oxygenase 1 in the protective effect of caloric restriction against diabetic cardiomyopathy. _Int. J. Mol. Sci._ 20, 2427 (2019). Article  PubMed  PubMed

Central  Google Scholar  * Li, D. et al. Fisetin attenuates doxorubicin-induced cardiomyopathy in vivo and in vitro by inhibiting ferroptosis through SIRT1/Nrf2 signaling pathway activation.

_Front. Pharmacol._ 12, 808480 (2022). Article  PubMed  PubMed Central  Google Scholar  * Docherty, K. F. et al. Effect of dapagliflozin on anaemia in DAPA-HF. _Eur. J. Heart Fail._ 23,

617–628 (2021). Article  CAS  PubMed  Google Scholar  * Yamada, T. et al. Analysis of time-dependent alterations of parameters related to erythrocytes after ipragliflozin initiation.

_Diabetol. Int._ 12, 197–206 (2020). Article  PubMed  PubMed Central  Google Scholar  * Kanamori, H. et al. Impact of autophagy on prognosis of patients with dilated cardiomyopathy. _J. Am.

Coll. Cardiol._ 79, 789–801 (2022). Article  CAS  PubMed  Google Scholar  * Hahn, V. S. et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction.

_Circulation_ 143, 120–134 (2021). Article  CAS  PubMed  Google Scholar  * Saito, T. et al. Autophagic vacuoles in cardiomyocytes of dilated cardiomyopathy with initially decompensated heart

failure predict improved prognosis. _Autophagy_ 12, 579–587 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Saito, T. et al. Long-term prognostic value of ultrastructural

features in dilated cardiomyopathy: comparison with cardiac magnetic resonance. _Esc. Heart Fail._ 7, 682–691 (2020). Article  PubMed  PubMed Central  Google Scholar  * Watanabe, T. et al.

Restriction of food intake prevents postinfarction heart failure by enhancing autophagy in the surviving cardiomyocytes. _Am. J. Pathol._ 184, 1384–1394 (2014). Article  CAS  PubMed  Google

Scholar  * Zhu, H. et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. _J. Clin. Invest._ 117, 1782–1793 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Nah, J. et al. Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart. _Cardiovasc. Res._ 118, 2638–2651 (2022). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Ghosh, R. et al. Chaperone mediated autophagy protects cardiomyocytes against hypoxic-cell death. _Am. J. Physiol. Cell Physiol._ 323, C1555–C1575 (2022). Article

  CAS  PubMed  Google Scholar  * Russo, M., Bono, E. & Ghigo, A. The interplay between autophagy and senescence in anthracycline cardiotoxicity. _Curr. Heart Fail. Rep._ 18, 180–190

(2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang, K. et al. Cardioprotection of Klotho against myocardial infarction-induced heart failure through inducing autophagy.

_Mech. Ageing Dev._ 207, 111714 (2022). Article  CAS  PubMed  Google Scholar  * Li, Q. et al. Hypoxia acclimation protects against heart failure postacute myocardial infarction via

Fundc1-mediated mitophagy. _Oxid. Med. Cell Longev._ 2022, 8192552 (2022). PubMed  PubMed Central  Google Scholar  * Li, L. et al. ATP6AP2 knockdown in cardiomyocyte deteriorates heart

function via compromising autophagic flux and NLRP3 inflammasome activation. _Cell Death Discov._ 8, 161 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Deng, Z. et al. DNA

methyltransferase 1 (DNMT1) suppresses mitophagy and aggravates heart failure via the microRNA-152-3p/ETS1/RhoH axis. _Lab. Invest._ 102, 782–793 (2022). Article  CAS  PubMed  Google Scholar

  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Baylor Heart and Vascular Institute, Dallas, TX, USA Milton Packer * Imperial College London, London, UK Milton Packer

Authors * Milton Packer View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Milton Packer. ETHICS DECLARATIONS

COMPETING INTERESTS During the past 3 years, M.P. has received consulting fees from AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring,

Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa and Salamandra, entirely related to the design and execution of clinical trials. PEER REVIEW PEER REVIEW INFORMATION _Nature

Reviews Cardiology_ thanks Gary Lopaschuk, Christoph Maack and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL INFORMATION PUBLISHER’S

NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a

society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript

version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Packer, M. SGLT2

inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism. _Nat Rev Cardiol_ 20, 443–462 (2023). https://doi.org/10.1038/s41569-022-00824-4 Download citation

* Accepted: 29 November 2022 * Published: 06 January 2023 * Issue Date: July 2023 * DOI: https://doi.org/10.1038/s41569-022-00824-4 SHARE THIS ARTICLE Anyone you share the following link

with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative