CHMP4C promotes pancreatic cancer progression by inhibiting necroptosis via the RIPK1/RIPK3/MLKL pathway

作者：Longchen Yu, Qining Guo, Yaping Li, Mai Mao, Zhenping Liu, Tingting Li, Lei Wang, Xin Zhang · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.01.040 · 被引用次数：24 · 研究领域：Cell death mechanisms and regulation、Nuclear Structure and Function、Ferroptosis and cancer prognosis

• CHMP4C promotes pancreatic cancer progression through inhibiting necroptosis and serves as a prognostic predictor for pancreatic cancer. • CHMP4C interacts with YBX1 to stabilize caspase-8 mRNA, and inhibits the RIPK1/RIPK3/MLKL pathway. • CHMP4C mediates the excretion of p-MLKL via extracellular vesicles. Pancreatic cancer (PC) cannot currently be completely cured and has a poor prognosis. Necroptosis is a distinct form of regulated cell death that differs from both necrosis and apoptosis. Understanding the role of necroptosis during PC progression would open new avenues for targeted therapy. The purpose of this study is to examine the impact of necroptosis on the progression of PC and related mechanisms. RNA sequencing was performed to identify necroptosis-related genes that are differentially expressed in PC tissues. The biological functions of CHMP4C and its necroptosis effects were determined in vitro and in vivo . RNA immunoprecipitation, MeRIP-qPCR, Co-immunoprecipitation assays were conducted to evaluate the interaction among CHMP4C, YBX1 and caspase-8 mRNA. Extracellular vesicles were isolated using the differential ultracentrifugation method. The expression of CHMP4C, p-MLKL and CD117 were detected on a PC tissue microarray using multiplex immunofluorescence staining. CHMP4C was significantly overexpressed in PC cells and tissues. It promoted cell growth and suppressed necroptosis of PC cells in both in vivo and in vitro settings. Mechanistically, CHMP4C interacte...