IRF1-mediated thioredoxin (TXN) protects multiple myeloma cells from ferroptosis through remodeling of PUFA-containing phospholipids

Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled plasma cell proliferation and frequent therapeutic relapse. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic vulnerability in cancer. However, the mechanisms governing ferroptosis resistance in MM remain incompletely understood. Here, we identified thioredoxin (TXN), a central redox regulator, as a ferroptosis suppressor associated with poor prognosis in MM patients. Genetic knockdown or pharmacological inhibition of TXN impaired MM progression and enhanced ferroptosis-associated lipid peroxidation. Mechanistically, TXN suppression induced broad remodeling of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), particularly phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species enriched in ferroptosis-relevant PUFAs, thereby increasing ferroptosis susceptibility. Rescue experiments using a redox-deficient TXN mutant further demonstrated that the ferroptosis-suppressive function of TXN depends on its redox activity. We further identified interferon regulatory factor 1 (IRF1), which is downregulated in MM, as a transcriptional repressor of TXN. IRF1 depletion increased TXN expression and partially attenuated TXN deficiency-induced lipid peroxidation, supporting the functional relevance of the IRF1-TXN axis in ferroptosis regulation. In addition, bortezomib (BTZ)-resistant MM cells exhibited elevated TXN expression and reduced ferroptosis sensitivity. Targeting TXN restored ferroptotic vulnerability and enhanced BTZ sensitivity in MM cells. Collectively, our findings identify TXN as a critical suppressor of ferroptosis-associated phospholipid remodeling and lipid peroxidation in MM and establish the IRF1-TXN axis as a potential therapeutic target for overcoming ferroptosis resistance and improving MM treatment outcomes.