IRF1-mediated thioredoxin (TXN) protects multiple myeloma cells from ferroptosis by regulating polyunsaturated fatty acids (PUFAs) and PUFA-containing phospholipid metabolism

Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled plasma cell proliferation. Patients with relapsed or refractory MM face poor survival, highlighting the need for novel therapeutic targets. Ferroptosis, an iron-dependent form of regulated cell death, is governed by a complex network of enzymes, proteins, pathways, and organelles, and has been implicated in various diseases. In this study, we identified thioredoxin (TXN), as a key suppressor of ferroptosis, was among the top ferroptosis-related genes linked to poor prognosis in MM patients. Functionally, TXN loss impaired MM progression by enhancing ferroptosis largely through regulating polyunsaturated fatty acids (PUFAs) and PUFA-containing phospholipids (PUFA-PLs), the major substrates for lipid peroxidation. TXN deficiency promoted ferroptosis by increasing PUFA biosynthesis and their incorporation into lipid peroxidation pathways. We further discovered that interferon regulatory factor 1 (IRF1), downregulated in MM, acts as a transcriptional repressor of TXN. Additionally, we demonstrated that bortezomib (BTZ)-resistant MM displayed elevated TXN expression, which enabled them to evade ferroptosis and diminished their sensitivity to BTZ. In conclusion, our findings revealed that IRF1-mediated regulation of TXN modulates PUFA/PUFA-PL metabolism to protect MM cells from ferroptosis, establishing TXN as a promising therapeutic target for overcoming ferroptosis resistance and improving treatment outcomes in MM.