IRX4204 sensitizes multiple myeloma to ferroptosis and improves lenalidomide efficacy through the HMOX1-GPX4 axis.

Despite advances in therapy, multiple myeloma (MM) largely remains incurable, emphasizing the need for new strategies to overcome drug resistance. Ferroptosis is an iron-dependent cell death pathway that may present a therapeutic vulnerability in MM, but its transcriptional regulation remains poorly understood. Retinoid X receptors (RXRs) are ligand-activated nuclear transcription factors that regulate metabolism, redox homeostasis, and immune signaling. In this study, we demonstrate that RXR signaling regulates ferroptosis. The selective third-generation RXR agonist IRX4204 significantly increased MM cells’ susceptibility to ferroptotic stress and worked synergistically with ferroptosis inducers. Mechanistic studies showed that IRX4204 actively induces HMOX1 transcription via PPARα-RXRα binding and concurrently decreases GPX4 levels, leading to iron buildup, lipid peroxidation, and ferroptosis. Deleting HMOX1 using CRISPR abolished these effects, confirming HMOX1 as an essential effector. In vivo, IRX4204 enhanced lenalidomide’s effectiveness, reduced tumor burden, extended survival, and elevated ferroptosis markers without added toxicity. Clinically, high HMOX1 expression correlates with improved overall survival in MM patients. These findings reveal a new RXR–HMOX1–GPX4 regulatory axis, establish RXR activation as a method to boost ferroptosis sensitivity, and support combining RXR agonists with ferroptosis-based treatments in MM.