Mitochondrial-inflammatory coupling in HFpEF: an emerging mechanistic framework for understanding the cardioprotective effects of SGLT2 inhibitors.

Heart failure with preserved ejection fraction (HFpEF) remains a major cause of cardiovascular morbidity and mortality, yet lacks effective disease-modifying therapies owing to pronounced biological heterogeneity. Emerging evidence indicates that HFpEF is not merely a disorder of diastolic dysfunction but a systemic immunometabolic condition characterized by mitochondrial energetic impairment, altered substrate utilization, and chronic low-grade inflammation. This review examines the potential role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in modulating mitochondrial-inflammatory coupling in HFpEF and proposes this axis as an emerging mechanistic framework that may contribute to their therapeutic effects. We review preclinical and clinical evidence suggesting that HFpEF is associated with coordinated immunometabolic reprogramming across cardiomyocytes, endothelial cells, and cardiac immune populations, which may contribute to mitochondrial-inflammatory uncoupling. We discuss evidence that SGLT2 inhibitors act beyond glycosuria to potentially improve myocardial energetic efficiency, enhance mitochondrial quality control, reduce oxidative stress, and attenuate maladaptive inflammatory signaling, including inflammasome activation. Collectively, these findings suggest that restoration of mitochondrial-inflammatory coupling may partly explain the clinical benefits of SGLT2 inhibitors in HFpEF, although direct mechanistic evidence in humans remains limited. Finally, we highlight emerging biomarkers and future therapeutic strategies targeting the mitochondrial-inflammatory axis to support the development of precision medicine approaches for HFpEF.