2. Academic Validation
  3. PSAT1 knockdown mediated VDAC1 oligomerization promotes ferroptosis and suppresses cell proliferation in esophageal squamous cell carcinoma

PSAT1 knockdown mediated VDAC1 oligomerization promotes ferroptosis and suppresses cell proliferation in esophageal squamous cell carcinoma

  • Int J Biol Macromol. 2025 Oct 7;330(Pt 4):148112. doi: 10.1016/j.ijbiomac.2025.148112.
Ruili Ren 1,  Tianli Fan 2,  Yiyang Li 1,  Changqun Li 1,  Fengdan Jin 1,  Hui Gao 3,  Xin Wang 4,  Yue Xu 5,  Xiangnan Li 6,  Shenglei Li 7,  Hongtao Liu 8
Affiliations

Affiliations

  • 1 School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
  • 2 Department of Pharmacology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
  • 3 Daytime Chemotherapy Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
  • 4 Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, PR China.
  • 5 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, PR China.
  • 6 Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, PR China. Electronic address: lxn-2000@163.com.
  • 7 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, PR China. Electronic address: lslbljys@126.com.
  • 8 School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, PR China. Electronic address: liuht1230@126.com.
PMID: 41061782 DOI: 10.1016/j.ijbiomac.2025.148112
Abstract

Phosphoserine aminotransferase 1 (PSAT1) has been widely implicated in the progression of various cancers. However, its functions and underlying mechanisms in esophageal squamous cell carcinoma (ESCC) remain poorly understood. Here, we found that PSAT1 was significantly upregulated in ESCC tissues and cell lines, and its expression was correlated with tumor grade and histological features of esophageal carcinoma (ESCA). Functionally, PSAT1 knockdown markedly suppressed cell proliferation, migration, invasion, and xenograft tumor growth, while promoting Ferroptosis in ESCC cells. Conversely, PSAT1 overexpression exerted opposing effects. Mechanistically, PSAT1 interacted with voltage-dependent anion channel 1 (VDAC1) in the cytoplasm of ESCC cells by molecular docking and Co-immunoprecipitation (Co-IP) and facilitated its degradation via the ubiquitin-proteasome pathway. Depletion of PSAT1 increased VDAC1 protein level and induced its oligomerization, leading to mitochondrial membrane potential (MMP) depolarization, cytosolic CA2+ accumulation, and mitochondrial permeability transition pore (MPTP) opening, ultimately resulting in mitochondrial dysfunction and Ferroptosis. Notably, pharmacological inhibition of VDAC1 by VBIT-12 abrogated PSAT1 silencing-induced Ferroptosis, confirming VDAC1 as a critical downstream mediator of PSAT1. In conclusion, our findings establish PSAT1 as a critical metabolic regulator that promotes ESCC progression by suppressing VDAC1-dependent Ferroptosis. Therefore, targeting the PSAT1-VDAC1 axis may offer a novel therapeutic approach for ESCC.

Keywords

Esophageal squamous cell carcinoma; Ferroptosis; Phosphoserine aminotransferase 1; Serine synthesis pathway; Voltage-Dependent Anion Channel 1.

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