2. Academic Validation
  3. DMNQ induces ferroptosis and augments the efficacy of anti-PD-L1 immunotherapy in gastric cancer via the STAT3/SLC1A4 axis to mediate cysteine metabolism reprogramming

DMNQ induces ferroptosis and augments the efficacy of anti-PD-L1 immunotherapy in gastric cancer via the STAT3/SLC1A4 axis to mediate cysteine metabolism reprogramming

  • Redox Biol. 2026 Mar:90:104055. doi: 10.1016/j.redox.2026.104055.
Wenshuai Zhu 1,  He Qi 2,  Fubo Jing 3,  Yuxuan Shi 3,  Yuanxin Xing 1,  Xiaoli Ma 1,  Bin Ning 4,  Yunshan Wang 5,  Yanfei Jia 6
Affiliations

Affiliations

  • 1 Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, People's Republic of China.
  • 2 Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, People's Republic of China; Department of Medical Laboratory, Shandong Second Medical University, Weifang, 261053, People's Republic of China.
  • 3 Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, 250013, People's Republic of China.
  • 4 Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University, Jinan, 250013, People's Republic of China.
  • 5 Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, People's Republic of China. Electronic address: [email protected].
  • 6 Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, People's Republic of China; Department of Medical Laboratory, Shandong Second Medical University, Weifang, 261053, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, 250013, People's Republic of China. Electronic address: [email protected].
PMID: 41604939 DOI: 10.1016/j.redox.2026.104055
Abstract

Ferroptosis plays an essential role in tumor progression. Therapeutic agents targeting Ferroptosis emerge as a novel strategy for Cancer treatment. Abnormal amino acid metabolism can control Ferroptosis sensitivity in Cancer cells, and lead to the deficiency or accumulation of specific products in the tumor microenvironment (TME). Here, we demonstrated that 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced growth inhibition in gastric Cancer cell lines, primary gastric Cancer mouse models, and patient-derived tumor organoids. DMNQ exerted Ferroptosis inducing effects by inhibiting STAT3 phosphorylation and transcriptional activity. Importantly, the STAT3/SLC1A4 axis regulated cysteine uptake, tumor killing by T cells and the efficacy of anti-PD-L1 immunotherapy. Collectively, our findings revealed a critical mechanism by which DMNQ exerts a significant anti-cancer role in gastric Cancer through increasing Ferroptosis to enhance Cancer Immunotherapy and may provide a novel therapeutic strategy for gastric Cancer.

Keywords

Anti-PD-L1 immunotherapy; Cysteine metabolism; DMNQ; Ferroptosis; STAT3/SLC1A4 axis.

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