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<p>Cisplatin resistance represents a major clinical challenge in small-cell lung cancer (SCLC), yet the underlying metabolic adaptations remain poorly understood. Here, we identify a novel regulatory axis centered on the fatty acid oxidation (FAO) enzyme carnitine palmitoyltransferase 1 A (<i>CPT1A</i>) that governs mitochondrial dynamics to drive chemoresistance. In cisplatin-resistant SCLC, <i>CPT1A</i> is markedly upregulated and undergoes functional acetylation. This modified CPT1A not only sustains cellular bioenergetics and redox balance through enhanced FAO but also directly recruits dynamin-related protein 1 (DRP1) to mitochondria. By facilitating DRP1-dependent mitochondrial fission, CPT1A orchestrates a metabolic adaptation that confers a survival advantage. Genetic or pharmacological inhibition of <i>CPT1A</i> reversed this phenotype, impairing mitochondrial fission, depleting energy stores, and resensitizing resistant cells to cisplatin. In vivo, targeting <i>CPT1A</i> markedly suppressed tumor growth and restored cisplatin sensitivity. Our results uncover an acetylated CPT1A-DRP1 axis as a critical metabolic vulnerability in cisplatin-resistant SCLC, providing a compelling therapeutic strategy to overcome treatment failure.</p>

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CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Kuanbing Chen,
  • Shi Zong,
  • Kefeng Li,
  • Li Yu

摘要

Cisplatin resistance represents a major clinical challenge in small-cell lung cancer (SCLC), yet the underlying metabolic adaptations remain poorly understood. Here, we identify a novel regulatory axis centered on the fatty acid oxidation (FAO) enzyme carnitine palmitoyltransferase 1 A (CPT1A) that governs mitochondrial dynamics to drive chemoresistance. In cisplatin-resistant SCLC, CPT1A is markedly upregulated and undergoes functional acetylation. This modified CPT1A not only sustains cellular bioenergetics and redox balance through enhanced FAO but also directly recruits dynamin-related protein 1 (DRP1) to mitochondria. By facilitating DRP1-dependent mitochondrial fission, CPT1A orchestrates a metabolic adaptation that confers a survival advantage. Genetic or pharmacological inhibition of CPT1A reversed this phenotype, impairing mitochondrial fission, depleting energy stores, and resensitizing resistant cells to cisplatin. In vivo, targeting CPT1A markedly suppressed tumor growth and restored cisplatin sensitivity. Our results uncover an acetylated CPT1A-DRP1 axis as a critical metabolic vulnerability in cisplatin-resistant SCLC, providing a compelling therapeutic strategy to overcome treatment failure.