Metabolic rewiring through succinate-GPR91 signaling: a fresh perspective on HFpEF energetics

Succinate has recently emerged as a signaling metabolite that extends beyond its canonical role in the tricarboxylic acid (TCA) cycle to influence cellular adaptation and stress responses. In their study, Jia et al. identify the succinate-GPR91 axis as a key regulator of cardiomyocyte metabolic reprogramming and NAD⁺ homeostasis in heart failure with preserved ejection fraction (HFpEF). Their findings suggest that restoring succinate-GPR91 signaling enhances mitochondrial energetics, improves redox balance, and alleviates diastolic dysfunction. This commentary discusses the significance of these results in the broader context of cardiometabolic disease, highlighting the conceptual novelty of metabolic rewiring as a form of cardioprotection, while also addressing unresolved questions regarding tissue specificity, long-term signaling balance, and translational potential. In recent years, succinate has emerged as a multifaceted player not merely a tricarboxylic acid (TCA) cycle intermediate but also a stress‑responsive metabolite that conveys cellular metabolic state to neighbouring cells and distant tissues. It accumulates during ischemia, hypoxia, or mitochondrial dysfunction and can drive reverse electron transport at complex I, thereby increasing reactive oxygen species (ROS) production [1, 3]. This biochemical duality on the one hand enabling damaging ROS generation, and on the other acting extracellularly via the G protein-coupled receptor GPR91-raises a central question: is succinate-GPR91 signaling protective, maladaptive, or fundamentally context‑dependent? Demonstrating that succinate can act extracellularly through GPR91 to reprogram cardiac metabolism would recast it from a metabolic by‑product into a bona fide signaling molecule with therapeutic implications. In this issue, Jia et al.² provide compelling evidence that the succinate-GPR91 axis functions as a molecular conduit linking mitochondrial metabolism to cardiomyocyte energy reprogramming, restoring NAD + and attenuating diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF).