Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance

Hwang, S.-Y.; Nikolli, H.; Yoval-Sanchez, B.; Yang, S.; Martin, P.; Gribbin, C.; Sehgal, L.; Alinari, L.; Baiocchi, R. A.; Hwang, I.; Huang, X.; DiLiberto, M.; Galkin, A.; Kwak, H.; Chen-Kiang, S.; Zheng, H.; Paik, J.

doi:10.1101/2025.09.02.673601

bioRxiv · 10.1101/2025.09.02.673601

Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance

Hwang, S.-Y.·Nikolli, H.·Yoval-Sanchez, B.·Yang, S.·Martin, P.·Gribbin, C.·Sehgal, L.·Alinari, L.·Baiocchi, R. A.·Hwang, I.·Huang, X.·DiLiberto, M.·Galkin, A.·Kwak, H.·Chen-Kiang, S.·Zheng, H.·Paik, J.

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Abstract

Resistance to Brutons 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.

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Hwang, S.-Y., Nikolli, H., Yoval-Sanchez, B., Yang, S., Martin, P., Gribbin, C., Sehgal, L., Alinari, L., Baiocchi, R. A., Hwang, I., Huang, X., DiLiberto, M., Galkin, A., Kwak, H., Chen-Kiang, S., Zheng, H., Paik, J.. 2025-09-05. Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance. https://doi.org/10.1101/2025.09.02.673601

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