ZEB2 SUMOylation in Cardiac Fibroblast Drives Post-Infarction Cardiac Remodeling through CtBP1-Associated repression...

The transcription factor ZEB2 has been implicated in cardiovascular disease, but its role and post-translational regulation in cardiac fibroblast-to-myofibroblast transition (FMT) and fibrosis after myocardial infarction (MI) are not fully understood. ZEB2 protein expression was significantly increased in infarcted murine hearts, activated cardiac fibroblasts, and human fibrotic myocardium. Myofibroblast-specific ZEB2 knockout alleviates cardiac dysfunction and adverse remodeling post-MI. Mechanistically, SENP1 regulated SUMO-1 modification of ZEB2 at K462, K479, K611, and K774. Reconstituting ZEB2-deficient systems with wild-type ZEB2 (ZEB2-WT) restored pathological fibrosis and FMT, whereas the SUMOylation-deficient mutant (ZEB2-4KR) conferred cardioprotective effects. ZEB2 SUMOylation activated the pro-fibrotic PI3K/AKT-mTORC1 signaling pathway. ZEB2-4KR weakens CtBP1 binding and enhances ZEB2 occupancy at the Nr4a1 promoter. Importantly, Nr4a1 knockdown abolished the protective effects of ZEB2-4KR. These findings identify SUMO-1 modification of ZEB2 as a central driver and molecular switch of pathological cardiac remodeling after MI and suggest that targeting ZEB2 SUMOylation may represent a promising therapeutic strategy.