Hypoxia-mediated SUMOylation of FADD exacerbates endothelial cell injury via the RIPK1-RIPK3-MLKL sig-naling axis

Vascular endothelial cells are the predominant cell type in the cardiovascular system, and endothelial dysfunction and death fol-lowing hypoxic injury lead to vascular lesions and play an essential role in the progression of cardiovascular disease. However, the mechanisms and specific interventions of vascular endothelial cell injury under hypoxia remain unclear. Here, we reported that hypox-ia induces the development of necroptosis and exacerbates in-flammatory injury in vascular endothelial cells in vivo and in vitro. We identified FADD as a critical regulator of hypoxia-mediated necroptosis, and the knockdown of FADD effectively reversed hy-poxia-induced necroptosis. Mechanistically, hypoxia affected pro-tein conformation through SUMOylation of FADD and competitively inhibited its ubiquitination, leading to an increase in protein half-life and protein level of FADD. On the other hand, SUMOylation in-creased the interaction between FADD and RIPK1 and induced the formation of the FADD-RIPK1-RIPK3 complex, thereby promoting necroptosis in vascular endothelial cells. The SUMOylation inhibi-tor ginkgolic acid (GA) notably reduced hypoxia-induced vascular endothelial injury and inflammatory responses in male mice. Take together, our research has uncovered a new process by which SUMOylation of FADD controls the occurrence of hypoxia-induced necroptosis in endothelial cells, which could identify new therapeu-tic targets for hypoxia-induced diseases.