Sun Danping, Cui Xiaohan, Yang Wenshuo, Wei Meng, Yan Zhibo, Zhang Mingxiang, Yu Wenbin
Department of Gastrointestinal Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China.
Cell Death Dis. 2025 Mar 26;16(1):208. doi: 10.1038/s41419-025-07562-8.
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.
胃癌的治疗仍然具有挑战性，免疫疗法是其整体治疗方法的关键组成部分。本研究结果表明，他汀类药物可降低胃癌患者血清中白细胞介素增强结合因子3（ILF3）和程序性细胞死亡配体1（PD-L1）水平，并改善其预后。功能实验表明，辛伐他汀通过抑制胃癌细胞中的ILF3诱导铁死亡，并增强活化的CD8 T细胞对胃癌细胞的杀伤作用。CUT&Tag分析显示，机制上，辛伐他汀通过降低ILF3中H3K14残基位点的乙酰化水平来抑制ILF3表达。下一代测序和京都基因与基因组百科全书分析显示，ILF3通过DEPTOR/mTOR信号通路调节PD-L1表达。总体而言，辛伐他汀通过抑制ILF3表达诱导胃癌细胞铁死亡，同时促进CD8 T细胞活化以增强抗肿瘤免疫反应，从而促进协同免疫治疗。
