PYRIN m⁶A modification drives cardiomyocyte PANoptosis in sepsis-induced cardiomyopathy

Sepsis-induced cardiomyopathy (SIC) is a major contributor to mortality in patients with sepsis, with PANoptosis-a form of inflammatory programmed cell death-emerging as a critical mechanism. This study investigated the upstream regulatory axis involving m⁶A RNA modification and its control of PYRIN expression in SIC. A murine SIC model was established via cecal ligation and puncture. Multiomics analyses, including RNA-seq, MeRIP-seq, RIP/MeRIP-qPCR, and luciferase reporter assays, were combined with in vivo genetic models (cardiomyocyte-specific knockout and AAV-mediated gene modulation) to elucidate the regulation of PYRIN and PANoptosis in cardiomyocytes. SIC induced PANoptosis, which was characterized by the simultaneous activation of apoptosis, pyroptosis, and necroptosis. PYRIN expression was significantly upregulated and was functionally required for PANoptosome formation. Mechanistically, FTO downregulation increased m⁶A methylation on PYRIN mRNA, enhancing its stability via the m⁶A reader IGF2BP2. Restoration of FTO expression or knockdown of IGF2BP2 expression suppressed PANoptosis and improved cardiac function. Furthermore, GATA4 was identified as a key transcriptional activator of FTO, and its downregulation in SIC underlies the initial FTO loss. This study reveals a novel GATA4-FTO/IGF2BP2-PYRIN axis that regulates cardiomyocyte PANoptosis in SIC. Targeting this pathway offers a promising strategy for therapeutic intervention in septic cardiac dysfunction.