{"title":"Simvastatin inhibits PD-L1 via ILF3 to induce ferroptosis in gastric cancer cells.","authors":"Danping Sun, Xiaohan Cui, Wenshuo Yang, Meng Wei, Zhibo Yan, Mingxiang Zhang, Wenbin Yu","doi":"10.1038/s41419-025-07562-8","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>+</sup> 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<sup>+</sup> T cells to augment antitumor immune responses, thereby facilitating synergistic immunotherapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"208"},"PeriodicalIF":8.1000,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947124/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-025-07562-8","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism.
Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following:
Experimental medicine
Cancer
Immunity
Internal medicine
Neuroscience
Cancer metabolism