O-GlcNAcylation of ASGR1 alleviates sepsis-induced cardiomyopathy via repressing ZBP1-mediated PANoptosis

Abstract Background Sepsis-induced cardiomyopathy (SICM) causes high critical mortality via excessive cardiomyocyte PANoptosis. Its upstream post-translational regulatory network remains unclear. Asialoglycoprotein receptor 1 (ASGR1) modulates inflammatory and cardiovascular lesions. Its expression regulatory cascade and PANoptosis-related function in SICM remain unexplored. Methods SICM patients were used for preliminary verification. Global and cardiomyocyte-specific ASGR1 knockout mice, ASGR1-knockout cardiomyocytes, and rescue assays defined the pathogenic function of ASGR1. Astral-DIA proteomics, RNA-seq, bioinformatic analysis, molecular docking, and dynamics simulations identified the O-GlcNAcylation site and binding proteins of ASGR1. Results Stabilized ASGR1 interacts with ZBP1 to initiate cardiomyocyte PANoptosis and worsen septic cardiac dysfunction. ASGR1 deletion or elevated O-GlcNAcylation reduces myocardial injury and improves survival in septic mice. LPS-mediated OGT reduction lowers T84 O-GlcNAcylation of ASGR1. This loss separates ASGR1 from the E3 ligase AMFR and blocks K48-linked proteasomal degradation, causing pathological ASGR1 accumulation. ASGR1 exerts cell-type-specific pro-PANoptotic effects in cardiomyocytes through cardiac OGT and AMFR-governed post-translational signaling. Distinct from our prior work on characterizing ASGR1-triggered neutrophil ferroptosis and NETosis, this study uncovers a cardiomyocyte-autonomous O-GlcNAcylation and ubiquitination crosstalk that is separate from immune inflammatory cascades. Conclusions This work identifies ASGR1 for the first time as an essential driver of cardiomyocyte PANoptosis that exacerbates septic cardiac dysfunction. Our findings address two key scientific questions in SICM. The first is the upstream cascade responsible for ASGR1 accumulation. The second is the ASGR1-ZBP1 signaling axis that drives myocardial PANoptosis. The OGT-ASGR1-ZBP1 regulatory cascade provides a promising therapeutic target for SICM treatment through post-translational modification modulation.