Heme-mediated liver-heart axis promotes myocardial pyroptosis in db/db mice

Diabetes, a systemic metabolic disorder, often involves multi-organ interactions in its complications. Although the pathogenesis of diabetic cardiomyopathy (DCM) is complex, the role of the liver in this process remains unclear. Using the db/db mouse model, this study demonstrated that metabolic dysfunction associated steatotic liver disease (MASLD) reduced hepatic synthesis of hemopexin (HPX) and impaired Kupffer cell function, leading to systemic heme accumulation. This circulating heme was taken up by cardiomyocytes via the membrane protein feline leukemia virus subgroup C receptor 2 (FLVCR2), which induced cardiomyocyte pyroptosis and aggravated myocardial injury. Intervention experiments indicated that targeted supplementation of hepatic HPX effectively restored heme homeostasis, reduced exogenous heme influx into cardiomyocytes, and improved cardiac function. These findings reveal a liver-heart axis mechanism in which hepatic heme mediates cardiomyocyte pyroptosis through FLVCR2, offering novel perspectives for the prevention and treatment of DCM.