Simvastatin inhibits PD-L1 via ILF3 to induce ferroptosis in gastric cancer cells

作者：Danping Sun, Xiaohan Cui, Wenshuo Yang, Wei Meng, Zhibo Yan, Mingxiang Zhang, Wenbin Yu · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07562-8 · 被引用次数：15 · 研究领域：Cancer, Lipids, and Metabolism、Ferroptosis and cancer prognosis、RNA modifications and cancer

Abstract The treatment of gastric cancer remains challenging, with immunotherapy serving as a critical component of the holistic approach to its treatment. The results of this study indicated that statins could decrease the serum levels of interleukin-enhancing binding factor 3 (ILF3) and programmed cell death ligand 1(PD-L1) in GC patients and improve their prognosis. Functional experiments demonstrated that simvastatin induced ferroptosis by inhibiting ILF3 in GC cells and enhanced the killing effect of activated CD8 + T cells on GC cells. The CUT&Tag assay revealed that, mechanistically, simvastatin inhibited ILF3 expression by reducing the acetylation level at residue site H3K14 in ILF3. Next-generation sequencing and Kyoto Encyclopedia of Genes and Genomes analysis revealed that ILF3 regulated PD-L1 expression through the DEPTOR/mTOR signaling pathway. Overall, simvastatin induced ferroptosis in GC cells by inhibiting ILF3 expression while promoting the activation of CD8 + T cells to augment antitumor immune responses, thereby facilitating synergistic immunotherapy.