Hyper-O-GlcNAcylation destabilizes ARC to unleash NLRP3-mediated pyroptosis in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes characterized by myocardial dysfunction and inflammatory cell death. While apoptosis repressor with caspase recruitment domain (ARC) is a known inhibitor of apoptosis, its potential role in regulating pyroptosis, a critical driver of diabetic cardiac injury-remains unexplored. In this study, we identified ARC as a potent endogenous suppressor of cardiomyocyte pyroptosis that is pathologically depleted in models of diabetes. Our findings demonstrated that overexpression of ARC, both in vitro and in diabetic mouse models, significantly alleviates high glucose-induced cardiomyocyte pyroptosis and cardiac dysfunction. We revealed that mechanistically, ARC binds to the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) via its CARD domain, thereby sequestering ASC and preventing NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly. However, under hyperglycemic conditions, we found that ARC undergoes aberrant O-GlcNAcylation at the Ser-104 residue. This modification destabilizes ARC by promoting its ubiquitin-proteasomal degradation, which subsequently releases ASC to trigger NLRP3-mediated pyroptosis. Furthermore, pharmacological inhibition of O-GlcNAcylation or restoration of ARC levels effectively rescued cardiomyocytes from pyroptotic death. In summary, our study elucidated a novel pathogenic "glucose-O-GlcNAc-ARC-pyroptosis" axis in DCM, revealing that hyperglycemia-induced O-GlcNAcylation compromises the protective function of ARC. These findings suggest that targeting the O-GlcNAc-ARC interaction represents a promising therapeutic strategy for diabetic cardiomyopathy.