Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

Dao-Fu Dai; Ines Martins; Nastaran Daneshgar; Meng Gao; Benjamin Rodriguez; Mohd Mabood Khan; Antentor Hinton Jr; Peter A. Crawford; Chad Grueter

doi:10.3390/cells15161478

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Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

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Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

Dao-Fu Dai, Ines Martins, Nastaran Daneshgar, Meng Gao, Benjamin Rodriguez, Mohd Mabood Khan, Antentor Hinton Jr, Peter A. Crawford and Chad Grueter

Cells (Basel, Switzerland), Vol.15(16), 1478

08/18/2026

DOI: 10.3390/cells15161478

PMID: 42645205

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Abstract

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.

sodium-glucose cotransporter-2 (SGLT2) inhibitors

Empagliflozine

myocardial infarction

heart failure

beta-hydroxybutyrate

ketone body oxidation

fibroblast growth factor-21

Details

Title: Subtitle: Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway
Creators: Dao-Fu Dai - Johns Hopkins University School of Medicine
Ines Martins - University of Iowa
Nastaran Daneshgar - University of Cincinnati Medical Center
Meng Gao - Johns Hopkins University
Benjamin Rodriguez - Vanderbilt University
Mohd Mabood Khan - Vanderbilt University
Antentor Hinton Jr - Vanderbilt University
Peter A. Crawford - University of Minnesota
Chad Grueter - University of Iowa
Resource Type: Journal article
Publication Details: Cells (Basel, Switzerland), Vol.15(16), 1478
DOI: 10.3390/cells15161478
PMID: 42645205
ISSN: 2073-4409
eISSN: 2073-4409
Publisher: MDPI
Grant note: Burroughs Welcome Fund (BWF): 1021868.01 KIAT: 2410008128 NIH: R01 DK133118
NIH R01 DK133118 (D.D), KIAT (2410008128 to DD), UNCF/Bristol-Myers Squibb E.E. Just Faculty Fund, Career Award at the Scientific Interface (CASI Award) from the Burroughs Welcome Fund (BWF) ID # 1021868.01 (to A.H.J).
Language: English
Date published: 08/18/2026
Academic Unit: Cardiovascular Medicine; Craniofacial Anomalies Research Center; Internal Medicine
Record Identifier: 9985219922202771

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