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

Oncogene volume 44, pages 2303–2314 (2025)Cite this article

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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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Fig. 1: Restoring FDX1 expression significantly promotes ES-induced DLBCL cell death.
Fig. 2: ES induces FDX1-dependent PANoptosis in DLBCL cells.
Fig. 3: FDX1 promotes the activation of IFN-β signaling in DLBCL cells upon ES treatment.
Fig. 4: FDX1 induces IRF3 activation upstream of IFN-β and promotes downstream PANoptosis and ISG induction.
Fig. 5: ES-induced death in FDX1-OE cells is dependent on IFN-β secretion.
Fig. 6: Restoration of FDX1 expression enhances the anticancer activity of ES in a mouse model.
Fig. 7: The protein levels of FDX1 and phosphorylated IRF3 were assessed in a human DLBCL tumor tissue microarray.

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Data availability

All data generated and/or analyzed during this study are included in this article and its supplemental material file. The RNA-seq datasets are available in the Gene Expression Omnibus (GEO) database (www.ncbi.nlm.nih.gov/geo) under accession nos. GSE228261 and GSE228263. Other data supporting the findings of this study are available from the corresponding authors.

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Acknowledgements

The authors thank Dr. Jiajia Xu for critical reading of the manuscript and for reagents. This work was supported by the National Natural Science Foundation of China (grant 32200723). This study was also partially supported by the Postdoctoral Starting Fund of the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Shanghai Municipal Health Commission Research Project (20194Y0242).

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  1. These authors contributed equally: Weifeng Chen, Yuhang Jiang, Jun Zeng.

Authors and Affiliations

  1. Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518, China

    Weifeng Chen, Jun Zeng, Yiqiu Cheng & Qi Wang

  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

    Weifeng Chen, Dandan Liu, Xiaoting Feng & Xiaoren Zhang

  3. Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, China

    Yuhang Jiang

  4. Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, China

    Di Lu

  5. Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Yangbai Sun

  6. Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 311599, China

    Qinyuan Zhu

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Contributions

WC, YJ and JZ contributed equally to this work. YJ and QW designed the research and conceived and coordinated the study; QW, WC, YC and DL performed the experiments; YJ, XF, and DL analyzed the data; JZ and YS performed the bioinformatic analyses. QW, YJ, XZ, QZ, and YS wrote the manuscript, which all other authors commented on.

Corresponding authors

Correspondence to Yangbai Sun, Qinyuan Zhu, Xiaoren Zhang or Qi Wang.

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The authors declare no competing interests.

Ethical approval

All animal experiments were approved by the Institute Research Ethics Committees of Sixth Affiliated Hospital of Guangzhou Medical University (LAEC-2021-011). A tissue microarray (TMA) containing 105 DLBCL samples was constructed by the Tissue Bank of the Fudan University Shanghai Cancer Center (FUSCC). This study was approved by the Medical Ethical Committee of FUSCC (FEC-20170314). Written informed consent was obtained from each patient in accordance with the Declaration of Helsinki.

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Chen, W., Jiang, Y., Zeng, J. et al. FDX1 promotes elesclomol-induced PANoptosis in diffuse large B-cell lymphoma via activating IRF3/IFN-β signaling. Oncogene 44, 2303–2314 (2025). https://doi.org/10.1038/s41388-025-03366-4

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