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<p>Ferroptosis is a unique modality of regulated cell death induced by excessive lipid peroxidation, playing a crucial role in tumor suppression and providing potential therapeutic strategy for cancer treatment. Here, we find that aldehyde dehydrogenase-ALDH3A1 tightly links to ferroptosis in squamous cell carcinomas (SCCs). Functional assays demonstrate the enzymatic activity-dependent regulation of ALDH3A1 in protecting SCC cells against ferroptosis through catalyzing aldehydes and mitigating lipid peroxidation. Furthermore, a specific covalent inhibitor of ALDH3A1-EN40 significantly enhances the ferroptosis sensitivity induced by the ferroptosis inducer. The combination of EN40 and a ferroptosis inducer exhibits a synergistic effect, effectively inhibiting the proliferation of SCC cells/organoids and suppressing tumor growth both in vitro and in vivo. On mechanism, high expression of <i>ALDH3A1</i> is transcriptionally governed by TP63, which binds to super-enhancer of <i>ALDH3A1</i>. Collectively, our findings reveal a yet-unrecognized function of ALDH3A1 exploited by SCC cells to evade ferroptosis, and targeting ALDH3A1 may enhance the effect of ferroptosis-induced therapy in SCCs.</p>

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Targeting aldehyde dehydrogenase ALDH3A1 increases ferroptosis vulnerability in squamous cancer

  • 期刊论文

  • 发表日期：

    2025年1月25日

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  • Shuai Kong,
  • Huaguang Pan,
  • Yuan-Wei Zhang,
  • Fei Wang,
  • Jian Chen,
  • Jinxiu Dong,
  • Chuntong Yin,
  • Jiaqi Wu,
  • Dan Zhou,
  • Jingyi Peng,
  • Junboya Ma,
  • Jianian Zhou,
  • Dianlong Ge,
  • Yan Lu,
  • Dan-Dan Wei,
  • Jinman Fang,
  • Wei Han,
  • Chengyin Shen,
  • H. Phillip Koeffler,
  • Boshi Wang,
  • Yuan Jiang,
  • Yan-Yi Jiang

摘要

Ferroptosis is a unique modality of regulated cell death induced by excessive lipid peroxidation, playing a crucial role in tumor suppression and providing potential therapeutic strategy for cancer treatment. Here, we find that aldehyde dehydrogenase-ALDH3A1 tightly links to ferroptosis in squamous cell carcinomas (SCCs). Functional assays demonstrate the enzymatic activity-dependent regulation of ALDH3A1 in protecting SCC cells against ferroptosis through catalyzing aldehydes and mitigating lipid peroxidation. Furthermore, a specific covalent inhibitor of ALDH3A1-EN40 significantly enhances the ferroptosis sensitivity induced by the ferroptosis inducer. The combination of EN40 and a ferroptosis inducer exhibits a synergistic effect, effectively inhibiting the proliferation of SCC cells/organoids and suppressing tumor growth both in vitro and in vivo. On mechanism, high expression of ALDH3A1 is transcriptionally governed by TP63, which binds to super-enhancer of ALDH3A1. Collectively, our findings reveal a yet-unrecognized function of ALDH3A1 exploited by SCC cells to evade ferroptosis, and targeting ALDH3A1 may enhance the effect of ferroptosis-induced therapy in SCCs.