Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC

Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Shencheng Ren, Haochun Shi, Xiaolong Huang, Junkan Zhu, Qun Wang, Wei Jiang (), Boyi Gan () and Cheng Zhan ()
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Guoshu Bi: Fudan University
Jiaqi Liang: Fudan University
Yunyi Bian: Fudan University
Guangyao Shan: Fudan University
Shencheng Ren: Fudan University
Haochun Shi: Fudan University
Xiaolong Huang: Fudan University
Junkan Zhu: Fudan University
Qun Wang: Fudan University
Wei Jiang: Fudan University
Boyi Gan: The University of Texas MD Anderson Cancer Center
Cheng Zhan: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN’s oxidoreductase function by occluding its active site. We also show that either restoring ALDH16A1 levels or inhibiting TXN significantly enhances the effectiveness of chemo/immunotherapy in a ferroptosis-dependent manner in SMARCA4-deficient NSCLC. Collectively, our findings elucidate an intricate SMARCA4-ALDH16A1-TXN stability/function dual regulatory axis that governs ferroptosis and informs a therapeutic strategy for overcoming resistance to chemotherapy or immunotherapy in SMARCA4-deficient NSCLC.

Date: 2025
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DOI: 10.1038/s41467-025-63687-6

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