Abstract
Resistance to Bruton's tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. Here, we identify ferroptosis suppression as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL). Aberrant BRG1 activity protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates NDUFA4L2 to inhibit mitochondrial respiration, thereby blocking mitochondria-dependent ferroptosis. Pharmacologic inhibition of BRG1 disrupts these programs, restoring ferroptotic sensitivity and synergizing with BTKi across resistant MCL models. Together, these findings establish BRG1 as a central regulator of therapy resistance and provide a rationale for co-targeting BRG1 and BTK as a therapeutic strategy for B-cell malignancies.