KLF15 activates PGC1α to rewire mitochondrial homeostasis and overcome cisplatin resistance in lung adenocarcinoma.

IF 10.4 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2026-06-27 DOI:10.1038/s41420-026-03235-3

Wan Lin, Lijuan Li, Yuwen Bai, Mai Wen, Wenjie Dong, Ruikun Ji, Jianqun Ma, Xiaodong Ling

{"title":"KLF15 activates PGC1α to rewire mitochondrial homeostasis and overcome cisplatin resistance in lung adenocarcinoma.","authors":"Wan Lin, Lijuan Li, Yuwen Bai, Mai Wen, Wenjie Dong, Ruikun Ji, Jianqun Ma, Xiaodong Ling","doi":"10.1038/s41420-026-03235-3","DOIUrl":null,"url":null,"abstract":"<p><p>Cisplatin resistance represents a major barrier to effective treatment of lung adenocarcinoma (LUAD), yet its metabolic underpinnings remain incompletely defined. Here, we demonstrate that the transcription factor KLF15 governs cisplatin sensitivity by orchestrating mitochondrial biogenesis and redox homeostasis. KLF15 is downregulated in cisplatin-resistant LUAD cells, which display reduced mitochondrial content and suppressed reactive oxygen species (ROS) accumulation. Restoring KLF15 expression resensitizes LUAD cells to cisplatin both in vitro and in vivo. Mechanistically, KLF15 directly transactivates PGC1α, and loss of PGC1α abrogates KLF15-mediated cisplatin sensitization, restoring drug resistance by attenuating apoptosis. Functionally, LUAD subpopulations with low mitochondrial mass or low KLF15 expression exhibit intrinsic resistance, whereas Mito-high xenografts show enhanced therapeutic response. Together, our findings identify a KLF15-PGC1α regulatory axis that dictates mitochondrial reprogramming and cisplatin responsiveness, highlighting a potential therapeutic axis to overcome chemoresistance in LUAD.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4000,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572412/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41420-026-03235-3","RegionNum":2,"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

Cisplatin resistance represents a major barrier to effective treatment of lung adenocarcinoma (LUAD), yet its metabolic underpinnings remain incompletely defined. Here, we demonstrate that the transcription factor KLF15 governs cisplatin sensitivity by orchestrating mitochondrial biogenesis and redox homeostasis. KLF15 is downregulated in cisplatin-resistant LUAD cells, which display reduced mitochondrial content and suppressed reactive oxygen species (ROS) accumulation. Restoring KLF15 expression resensitizes LUAD cells to cisplatin both in vitro and in vivo. Mechanistically, KLF15 directly transactivates PGC1α, and loss of PGC1α abrogates KLF15-mediated cisplatin sensitization, restoring drug resistance by attenuating apoptosis. Functionally, LUAD subpopulations with low mitochondrial mass or low KLF15 expression exhibit intrinsic resistance, whereas Mito-high xenografts show enhanced therapeutic response. Together, our findings identify a KLF15-PGC1α regulatory axis that dictates mitochondrial reprogramming and cisplatin responsiveness, highlighting a potential therapeutic axis to overcome chemoresistance in LUAD.

查看原文本刊更多论文

KLF15激活PGC1α重建线粒体稳态并克服肺腺癌的顺铂耐药。

顺铂耐药是肺腺癌（LUAD）有效治疗的主要障碍，但其代谢基础仍未完全确定。在这里，我们证明转录因子KLF15通过协调线粒体生物发生和氧化还原稳态来控制顺铂敏感性。在顺铂耐药LUAD细胞中，KLF15下调，线粒体含量降低，活性氧（ROS）积累受到抑制。在体外和体内，恢复KLF15表达可使LUAD细胞对顺铂重新敏感。在机制上，KLF15直接激活PGC1α， PGC1α的缺失消除了KLF15介导的顺铂致敏作用，通过减轻细胞凋亡来恢复耐药。在功能上，低线粒体质量或低KLF15表达的LUAD亚群表现出内在抗性，而mito -高的异种移植物表现出增强的治疗反应。总之，我们的研究结果确定了一个KLF15-PGC1α调节轴，它决定了线粒体重编程和顺铂反应性，突出了克服LUAD化疗耐药的潜在治疗轴。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.