Sestrin2 mitigates obesity-associated HFpEF via adaptive IRE1α-XBP1 signaling and redox regulation.

Obesity-associated heart failure with preserved ejection fraction (HFpEF) is a metabolic cardiac disorder characterized by diastolic dysfunction. Sestrin2 is a stress-inducible regulator of metabolic and redox homeostasis, but its role in HFpEF remains incompletely defined. This study demonstrates that Sestrin2 has cardioprotective effects on obesity-associated HFpEF. In an obesity-associated HFpEF mouse model, cardiac Sestrin2 overexpression attenuates diastolic dysfunction, myocardial lipid accumulation, fibrosis, hypertrophy, and mitochondrial dysfunction without significantly affecting adiposity, circulating lipid levels, or whole-body substrate utilization. Mechanistically, Sestrin2 overexpression increases IRE1α phosphorylation and XBP1 splicing, indicating enhanced adaptive unfolded protein response signaling. Sestrin2 overexpression is also associated with increased Sigma-1 receptor (Sigmar1) expression, whereas Sigmar1 knockdown attenuates Sestrin2-associated IRE1α-XBP1 activation in vitro, suggesting the involvement of Sigmar1 in endoplasmic reticulum-mitochondrial stress adaptation. In addition, Sestrin2 overexpression enhances AMPK activation, increases acetyl-CoA carboxylase (AAC) and eNOS phosphorylation, suppresses mTOR signaling, enhances Nrf2-HO-1 antioxidant responses, and reduces inflammatory marker expression and mitochondrial ROS production. Metabolomic analysis further reveals partial alterations in metabolites associated with endoplasmic reticulum stress and redox homeostasis. Collectively, these findings suggest that Sestrin2 alleviates obesity-associated HFpEF and is associated with the activation of adaptive IRE1α-XBP1 signaling involving Sigmar1, together with improved metabolic and redox homeostasis.