Authors
Soo-Yeon Hwang, Xiangao Huang, Helgi Nikolli, Belem Yoval-Sánchez, Sieun Yang, Jeongbin Heo, Peter Martin, Caitlin Gribbin, Preetesh Jain, Michael Wang, Lalit Sehgal, Robert A Baiocchi, Inah Hwang, Maurizio DiLiberto, Alexander Galkin, Hojoong Kwak, Lapo Alinari, Selina Chen-Kiang, Hongwu Zheng, Jihye Paik
Published in
Nature communications. Jul 02, 2026. Epub Jul 02, 2026.
Abstract
Resistance to Bruton's tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies. Here, we identify chromatin remodeler BRG1-mediated suppression of ferroptosis as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL), in which aberrant BRG1-dependent transcription program protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through regulation of both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates atypical mitochondrial complex I subunit NDUFA4L2. Increased NDUFA4L2 restricts cellular respiration, preemptively limiting mitochondrial ROS generation and activating AMPK signaling, together reducing susceptibility to lipid peroxidation and ferroptosis. Pharmacologic inhibition of BRG1 disrupts these programs, restoring ferroptotic sensitivity and synergizing with BTKi across resistant MCL models. Together, our study establishes BRG1 as a central regulator of BTKi resistance and provides a rationale for co-targeting BRG1 and BTK as a therapeutic strategy for B-cell malignancies.
PMID:
42393054
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.
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