2. Academic Validation
  3. ALDH3A2 negatively orchestrates gastric cancer progression through a synergistic induction of ferroptosis and ferroptosis-driven macrophage reprogramming

ALDH3A2 negatively orchestrates gastric cancer progression through a synergistic induction of ferroptosis and ferroptosis-driven macrophage reprogramming

  • Cell Death Dis. 2025 Dec 24. doi: 10.1038/s41419-025-08364-8.
Yuanyuan Ren # 1,  Yue Cui # 1,  Zhen Wang 1 2,  Yizhi Luo 1,  Junchang Jin 1,  Yiyi Yuan 1,  Xuan Li 1,  Yaning Zhang 1,  Nan Cao 1 3,  Xiaofang Li 4,  Yi Yu 5 6,  Yuyan Xiong 7 8
Affiliations

Affiliations

  • 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, PR China.
  • 2 Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, PR China.
  • 3 School of Medicine, Northwest University, Xi'an, Shaanxi, PR China.
  • 4 Department of Gastroenterology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, PR China.
  • 5 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, PR China. [email protected].
  • 6 School of Medicine, Northwest University, Xi'an, Shaanxi, PR China. [email protected].
  • 7 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, PR China. [email protected].
  • 8 Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, PR China. [email protected].
  • # Contributed equally.
PMID: 41444219 DOI: 10.1038/s41419-025-08364-8
Abstract

Gastric Cancer (GC) is a prevalent gastrointestinal malignancy in which Ferroptosis, mitochondrial dysfunction, and macrophage reprogramming remarkably contribute to disease progression. However, the molecular interplay among these processes in contributing to GC remains poorly understood. In this study, we identified ferroptosis- and mitochondrial dysfunction-related genes (FMDRGs) implicated in GC through bioinformatics analyses. Among them, aldehyde dehydrogenase 3 family member A2 (ALDH3A2) was identified as a key FMDRG significantly downregulated in GC tissues and cell lines. Functional assays revealed that ALDH3A2 overexpression in GC cell lines suppressed proliferation, migration, and invasion while enhancing Ferroptosis, effects that were reversed by GPX4 overexpression. ALDH3A2 also impaired the mitochondrial unfolded protein response (UPRmt) and induced mitochondrial dysfunction. Restoration of UPRmt ameliorated ALDH3A2-induced mitochondrial dysfunction and Ferroptosis. Mechanistically, ALDH3A2 impaired UPRmt by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and subsequent Ferroptosis. Synergistically, ALDH3A2-induced Ferroptosis promoted IL-6 release, which drove macrophage polarization toward the M1 phenotype with elevated IL-1β production. This macrophage reprogramming, in turn, inhibited GC cell progression by downregulating PD-L1 expression. Therapeutically, both genistein treatment and ALDH3A2 overexpression significantly attenuated GC progression in vitro and in vivo. These findings elucidate ALDH3A2 as a dual regulator of tumor-intrinsic Ferroptosis and tumor-extrinsic immune remodeling in contributing to GC pathogenesis, highlighting its potential as a promising therapeutic target in GC.

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