2. Academic Validation
  3. Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC

Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC

  • Protein Cell. 2025 Nov 19:pwaf101. doi: 10.1093/procel/pwaf101.
Peng Wang 1 2,  Shengdan Zhang 3,  Xin Chen 4,  Xu-Dong Yang 1,  Shi Huang 1,  Huiyong Yin 4,  Hao-Yu Duan 1,  Fuling Zhou 2,  Jia Yu 5,  Bo Zhong 1 6,  Dandan Lin 1
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Cancer Center, Renmin Hospital of Wuhan University, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, Wuhan University, Wuhan, 430071, China.
  • 2 Research Center for Lifespan Health, School of Nursing, Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
  • 3 Department of Stomatology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 4 AS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 5 Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 6 TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
PMID: 41259048 DOI: 10.1093/procel/pwaf101
Abstract

Glutathione Peroxidase 4 (GPX4) is a master regulator of Ferroptosis, a process that has been proposed as a potential therapeutic strategy for Cancer. Here we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung Cancer (NSCLC) progression in the autochthonous Kras LSL-G12D/+ Lkb1 fl/fl (KL) and Kras LSL-G12D/+ Tp53 fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade Ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8+ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to Ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.

Keywords

GPX4; lipid droplets; lipid release; non-small cell lung cancer; triacylglycerol; tumor microenvironment.

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