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<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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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

摘要

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.