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Updated: Sep 9, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in
Guoshu Bi1, Jiaqi Liang1, Yunyi Bian1
1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
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.
Insights
SMARCA4 deficiency in lung cancer sensitizes cells to ferroptosis by regulating ALDH16A1 and thioredoxin (TXN). Restoring ALDH16A1 or inhibiting TXN enhances chemo/immunotherapy effectiveness in ferroptosis-resistant cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ferroptosis, a regulated cell death pathway, is a promising cancer therapy target.
- The role of tumor suppressors like SMARCA4 in ferroptosis and cancer treatment resistance is not fully understood.
Purpose of the Study:
- To investigate the mechanism by which SMARCA4 deficiency impacts ferroptosis in non-small cell lung cancer (NSCLC).
- To identify therapeutic strategies to overcome treatment resistance in SMARCA4-deficient NSCLC.
Main Methods:
- Analysis of SMARCA4's role in regulating ferroptosis.
- Investigating the interaction between SMARCA4, ALDH16A1, and thioredoxin (TXN).
- Assessing the therapeutic potential of modulating ALDH16A1 or TXN in NSCLC models.
Main Results:
- SMARCA4 deficiency sensitizes NSCLC cells to ferroptosis by upregulating ALDH16A1.
- ALDH16A1 targets the anti-ferroptotic protein TXN for lysosomal degradation and inhibits its function.
- Restoring ALDH16A1 or inhibiting TXN enhances chemo/immunotherapy efficacy in a ferroptosis-dependent manner.
Conclusions:
- A novel SMARCA4-ALDH16A1-TXN regulatory axis controls ferroptosis.
- Targeting this axis offers a therapeutic strategy for SMARCA4-deficient NSCLC, potentially overcoming chemo/immunotherapy resistance.
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