高-O-GlcNA酰化使ARC不稳定，从而在糖尿病心肌病中释放NLRP 3介导的焦亡
高-O-GlcNA酰化使ARC不稳定，从而在糖尿病心肌病中释放NLRP3介导的焦亡
作者： 小柯机器人 发布时间：2026/8/13 15:48:40
本期文章：《中国药理学报》：Online/在线发表
青岛大学王建勋小组发现了高-O-GlcNA酰化使ARC不稳定，从而在糖尿病心肌病中释放NLRP3介导的焦亡。这一研究成果于2026年8月12日发表在国际顶尖学术期刊《中国药理学报》上。
在这项研究中，研究组发现ARC是一种有效的内源性抑制因子，可以抑制糖尿病模型中病理缺失的心肌细胞焦亡。他们的研究结果表明，在体外和糖尿病模型中，过表达ARC可显著减轻高糖诱导的心肌细胞焦亡和心功能障碍。课题组人员发现，在机制上，ARC通过其CARD结构域与含有CARD的接头蛋白凋亡相关斑点样蛋白（ASC）结合，从而隔离ASC并阻止含有3（NLRP3）炎症小体的NOD样受体家族pyrin结构域组装。
然而，在高血糖条件下，小组发现ARC在Ser-104残基处发生了异常的O-GlcNA酰化。这种修饰通过促进其泛素-蛋白酶体降解来破坏ARC的稳定性，随后释放ASC以触发NLRP3介导的焦亡。
此外，药物抑制O-GlcNA酰化或恢复ARC水平可以有效地拯救心肌细胞免于焦亡。总之，他们的研究阐明了DCM中一个新的致病“葡萄糖-O-GlcNAc-ARC-热分解”轴，揭示了高血糖诱导的O-GlcNA酰化损害了ARC的保护功能。这些发现表明，靶向O-GlcNAc-ARC相互作用是治疗糖尿病性心肌病的一种有希望的治疗策略。
据悉，糖尿病性心肌病（DCM）是糖尿病的严重并发症，以心肌功能障碍和炎症细胞死亡为特征。虽然含有胱天蛋白酶募集结构域（ARC）的细胞凋亡抑制因子是一种已知的细胞凋亡抑制剂，但其在调节焦亡（糖尿病心脏损伤的关键驱动因素）中的潜在作用仍未被探索。
附：英文原文
Title: Hyper-O-GlcNAcylation destabilizes ARC to unleash NLRP3-mediated pyroptosis in diabetic cardiomyopathy
Author: Ye, Lin, Li, Meng-yang, Ao, Xiang, Xiao, Dan-dan, Wang, Yu, Wang, Pei-yan, Li, Qi, Ding, Wei, Wang, Jian-xun
Issue&Volume: 2026-08-12
Abstract: 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.
DOI: 10.1038/s41401-026-01883-w
Source: https://www.nature.com/articles/s41401-026-01883-w