2. Academic Validation
  3. FDX1 promotes elesclomol-induced PANoptosis in diffuse large B-cell lymphoma via activating IRF3/IFN-β signaling

FDX1 promotes elesclomol-induced PANoptosis in diffuse large B-cell lymphoma via activating IRF3/IFN-β signaling

  • Oncogene. 2025 Jul;44(27):2303-2314. doi: 10.1038/s41388-025-03366-4.
Weifeng Chen # 1 2,  Yuhang Jiang # 3,  Jun Zeng # 1,  Dandan Liu 2,  Xiaoting Feng 2,  Yiqiu Cheng 1,  Di Lu 4,  Yangbai Sun 5,  Qinyuan Zhu 6,  Xiaoren Zhang 7,  Qi Wang 8
Affiliations

Affiliations

  • 1 Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518, China.
  • 2 Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, 511495, China.
  • 3 Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, China.
  • 4 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
  • 5 Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. drsunyb@fudan.edu.cn.
  • 6 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 311599, China. memi942@163.com.
  • 7 Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, 511495, China. xrzhang@gzhmu.edu.cn.
  • 8 Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518, China. wq131415@qq.com.
  • # Contributed equally.
PMID: 40240522 DOI: 10.1038/s41388-025-03366-4
Abstract

Diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge and requires the development of new therapeutic approaches. The identification of Cuproptosis, a newly defined form of copper-induced cell death, has provided innovative insights for Cancer therapy. Here, we report that loss of the mitochondrial matrix reductase FDX1 in DLBCL cells impairs the antitumor effect of elesclomol (ES), which performs its function by transporting excess copper into cells. Overexpressing (OE) FDX1 significantly sensitized DLBCL cells to ES-induced cell death in vitro and enhanced the Anticancer activity of ES in vivo. Furthermore, treatment with ES in FDX1-high expression patient-derived xenograft (PDX) showed a significantly greater inhibitory effect than in FDX1-low expression PDX. Mechanistically, FDX1 promotes the induction of IFN-β-dependent PANoptosis by increasing IRF3 phosphorylation in DLBCL cells upon ES treatment. Consistent with this finding, patient cohort analysis revealed that FDX1 expression correlated positively with enhanced IRF3 phosphorylation. Together, our findings are the first to identify the central role of FDX1 in synergizing with ES to activate IFN-β signaling and induce PANoptosis. This study enables us to re-explore the clinical Anticancer potential of ES as a novel therapeutic strategy for DLBCL.

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