FDXR upregulation by p63/p73 is a prognostic and therapeutic marker of adult T-cell leukemia/lymphoma.

Infection with HTLV-1 can lead to severe diseases, including adult T-cell leukemia/lymphoma (ATL), for which current therapies are inadequate. Selective elimination of chronically infected cells requires identifying cellular markers dysregulated by HTLV-1 that can be exploited therapeutically. Combining metabolomics and proteomics analyses, we identified increased expression of the mitochondrial enzyme ferredoxin reductase (FDXR) as a hallmark of HTLV-1-infected cells. In patient cells, FDXR upregulation mirrored disease severity, was enriched in proliferating tumour cells and predicted worse ATL prognosis. Mechanistically, FDXR upregulation in ATL cells is driven by the transactivating isoforms of two p53 family members, TAp63 and TAp73, and TAp63 expression is, in turn, induced by the IRF4/BATF3 transcriptional axis. In silico drug susceptibility predictions, followed by targeted cytotoxicity, proliferation and Drug-Seq assays demonstrated that FDXR upregulation is associated with increased sensitivity of ATL cells to repurposed chemotherapeutic agents, particularly fluorouracil. Overall, our findings establish FDXR as a novel biomarker of HTLV-1-associated disease progression and ATL prognosis, elucidate its upstream molecular regulation, and highlight its predictive potential for chemotherapeutic sensitivity of ATL cells.