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

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 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 Ca 2+ 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.