2. Academic Validation
  3. Copper potentiates PUFA-mediated antitumor activity by activating Lipophagy

Copper potentiates PUFA-mediated antitumor activity by activating Lipophagy

  • Cell Signal. 2026 Jun:142:112454. doi: 10.1016/j.cellsig.2026.112454.
Xiangyang He 1,  Qianqian Yang 2,  Xiaowen Lin 1,  Ziyuan Chen 1,  Kaixuan Ren 1,  Jiao Yang 1,  Xiaoqin An 3,  Shangzhu Yang 3,  Li Yang 3,  Qian Xue 1,  Xi Chen 1,  Yuan Wang 1,  Guifang Yu 4,  Ding Yan 5,  Xin Chen 6
Affiliations

Affiliations

  • 1 Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, Guangdong, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, Guangdong, China.
  • 2 Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China.
  • 3 Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Anshun 561113, Guizhou, China.
  • 4 Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, Guangdong, China. Electronic address: [email protected].
  • 5 Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, Guangdong, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, Guangdong, China. Electronic address: [email protected].
  • 6 Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, Guangdong, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, Guangdong, China. Electronic address: [email protected].
PMID: 41765311 DOI: 10.1016/j.cellsig.2026.112454
Abstract

Polyunsaturated fatty acids (PUFAs) have demonstrated promising Anticancer properties by inducing Cancer cell death and inhibiting Cancer metastasis. As dynamic organelles, lipid droplets (LDs) may protect cells from PUFA-induced lipotoxicity by sequestering excess fatty acids. However, the underlying mechanisms regulating LDs dynamics in PUFA-mediated tumor cytotoxicity remain poorly understood. In this study, we report that inhibition of LDs synthesis enhances PUFA-induced Cancer cell death, suggesting that LDs formation protects against PUFA cytotoxicity. We further demonstrate that copper ions potentiate the antitumor effects of PUFAs across multiple Cancer cell lines primarily by promoting Apoptosis rather than Cuproptosis or Ferroptosis. Mechanistically, copper ions significantly reduce intracellular LDs accumulation by promoting LDs degradation via activation of ATGL-dependent lipophagy. Collectively, these findings uncover a novel mechanism whereby copper ions enhance PUFA-induced tumor cell death through promoting lipophagy, which provides valuable insights for optimizing PUFA-based Cancer therapies by targeting lipid metabolism and copper homeostasis.

Keywords

Copper; Lipophagy; PUFA; Tumor.

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