Fibroblasts‐specific p16 INK4a exacerbates inflammageing‐mediated post‐infarction ventricular remodelling through interacting with STAT3 to regulate NLRP3 transcription

作者：Xin Gu, Yingqiang Du, Jinge Zhang, Jiyu Li, Haiyun Chen, Yujie Lin, Yue Wang, Chunli Zhang, Shiyu Lin, Nannan Hao, Chengyi Peng, Jiacheng Ge, Jin Liu, Yan Liang, Yongjie Zhang, Xiaoyan Wang, Fang Wang, Jianliang Jin · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70344 · 被引用次数：6 · 研究领域：Cardiac Fibrosis and Remodeling、Signaling Pathways in Disease、Cardiovascular Function and Risk Factors

Abstract Background and Aims Inflammageing represents both a critical pathophysiological hallmark and independent risk factor for myocardial infarction (MI), with age‐related increases observed in MI incidence and severity of post‐MI ventricular remodelling. Novel therapeutic strategies targeting inflammageing‐driven mechanisms are urgently required to attenuate adverse ventricular remodelling following MI. This investigation was designed to elucidate the impact of fibroblast‐specific p16 INK4a on inflammageing‐associated ventricular remodelling after MI and to develop a targeted nanotherapy to mitigate this process. Methods and Results We found that p16‐mediated inflammageing positively correlated with the severity of post‐infarction ventricular remodelling in patients. POSTN ‐driven p16 INK4a knockout improved cardiac function, and reduced ventricular remodelling, myocardial inflammation and NLRP3 signalling activation following MI through downregulating STAT3‐mediated NLRP3 inflammasome and upregulating glutathione metabolism pathway in fibroblasts. P16 INK4a overexpression induced NLRP3 signalling activation through upregulating NLRP3 transcribed by STAT3 in fibroblasts. In terms of mechanisms, p16 INK4a interacted with STAT3, which depended on the SH2 domain of STAT3; P16 INK4a promoted the interaction of EZH2 and STAT3, increased the di‐methylation on K49 and phosphorylation on Y705 of STAT3 by EZH2, and promoted NLRP3 transcription through regulating histone modificati...