Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway.
DF, D., I, M., N, D., M, G., B, R., MM, K., Jr, H.A., PA, C., & C, G. (2026). Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway.. Cells. https://doi.org/10.3390/cells15161478
DF D, I M, N D, M G, B R, MM K, et al. Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway.. Cells. 2026; doi: 10.3390/cells15161478
DF D, I M, N D, et al. Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway.[J]. Cells. 2026. DOI: 10.3390/cells15161478.
@article{df2026,
author = {Dai DF and Martins I and Daneshgar N and Gao M and Rodriguez B and Khan MM and Hinton A Jr and Crawford PA and Grueter C},
title = {Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway.},
journal = {Cells},
year = {2026},
doi = {10.3390/cells15161478},
note = {PMID: 42645205},
}
TY - JOUR AU - Dai DF AU - Martins I AU - Daneshgar N AU - Gao M AU - Rodriguez B AU - Khan MM AU - Hinton A Jr AU - Crawford PA AU - Grueter C TI - Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway. T2 - Cells PY - 2026 DO - 10.3390/cells15161478 AN - PMID:42645205 ER -
Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure, but the mechanisms remain incompletely understood. Metabolic remodeling has been proposed as a key mediator. Methods and Results: Myocardial infarction (MI) was induced in cardiomyocyte-specific BDH1 knockout (BDH1-KO) wild-type (WT) mice and in liver-specific Fibroblast Growth Factor-21 knockout (FGF21-KO) mice. Following confirmation of reduced ejection fraction (EF), mice were randomized to empagliflozin (Empa, 10 mg/kg/day) or saline. After 4 weeks, untreated WT mice demonstrated progressive systolic dysfunction (ΔEF: -11.6 ± 6.3%), whereas Empa-treated WT mice showed significant improvement (ΔEF: 9.9 ± 4.3%). This benefit was completely abolished in BDH1-KO mice (ΔEF: -10.5 ± 2.8%) or FGF21-KO mice, suggesting that FGF21 regulation and cardiomyocyte ketone oxidation are required for Empa cardioprotection. In WT and hepatocyte-specific FGF21-KO mice, 1 week of Empa treatment increased cardiac BDH1 expression in WT but not FGF21-deficient mice. In human iPSC-cardiomyocytes, FGF21 induced BDH1 expression, whereas Empa had no direct effect on BDH1. In HepG2 liver cells, Empa increased both FGF21 and BDH1 expression. Conclusions: Empa activates the liver-heart metabolic axis. Loss of cardiomyocyte BDH1 or FGF21 production by the liver abolishes Empa-mediated improvement in post-MI cardiac function, identifying FGF21/ketone metabolism as a key mechanism of SGLT2 inhibitor cardioprotection.