Targeting aldehyde dehydrogenase ALDH3A1 increases ferroptosis vulnerability in squamous cancer

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

doi:10.1038/s41388-025-03277-4

Targeting aldehyde dehydrogenase ALDH3A1 increases ferroptosis vulnerability in squamous cancer

Oncogene. 2025 Jan 25. doi: 10.1038/s41388-025-03277-4. Online ahead of print.

Authors

Shuai Kong^#^{1

2}, Huaguang Pan^#³, Yuan-Wei Zhang^#¹, Fei Wang^{1

2}, Jian Chen¹, Jinxiu Dong¹, Chuntong Yin^{1

3}, Jiaqi Wu¹, Dan Zhou¹, Jingyi Peng^{1

2}, Junboya Ma^{1

2}, Jianian Zhou^{1

2}, Dianlong Ge¹, Yan Lu¹, Dan-Dan Wei^{1

2

4}, Jinman Fang^{1

2

4}, Wei Han¹, Chengyin Shen¹, H Phillip Koeffler⁵, Boshi Wang⁶, Yuan Jiang^{7

8}, Yan-Yi Jiang^{9

10}

Affiliations

¹ Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
² University of Science and Technology of China, Hefei, 230026, China.
³ Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
⁴ Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China.
⁵ Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁶ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China. wbs137@shsci.org.
⁷ Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. yuanj@cmpt.ac.cn.
⁸ University of Science and Technology of China, Hefei, 230026, China. yuanj@cmpt.ac.cn.
⁹ Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. yanyij@cmpt.ac.cn.
¹⁰ University of Science and Technology of China, Hefei, 230026, China. yanyij@cmpt.ac.cn.

^# Contributed equally.

PMID: 39863749
DOI: 10.1038/s41388-025-03277-4

Abstract

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.

Abstract

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