Work

Phosphatidylserine Decarboxylase Promotes Ferroptosis Through STAT3/GPX4 Signaling in Gastric Cancer

Year: 2026

Type: article

Abstract: Gastric cancer (GC) remains a major global health burden, and increasing evidence suggests that ferroptosis plays an important role in regulating tumor cell survival. Phosphatidylserine decarboxylase (PISD) is a key mitochondrial enzyme responsible for phosphatidylethanolamine (PE) synthesis; however, its molecular function in GC remains poorly understood. In this study, we suggest that downregulation of PISD is associated with enhanced ferroptosis in GC cells by disrupting mitochondrial PE homeostasis and impairing mitochondrial function. Mechanistically, PISD depletion reduces PE levels, is accompanied by a reduction in signal transducer and activator of transcription 3 (STAT3) phosphorylation, and decreases GPX4 expression, leading to enhanced lipid peroxidation, iron accumulation, and redox imbalance. Pharmacological inhibition of ferroptosis using Ferrostatin-1 (Fer-1), activation of STAT3 by ML115, or supplementation with lysophosphatidylethanolamine (LPE) partially rescues PISD knockdown-induced ferroptosis. In vivo, PISD downregulation is significantly accompanied by a reduction in tumor growth in GC xenograft models. Collectively, our findings reveal a previously unrecognized role of PISD in linking mitochondrial phospholipid metabolism to STAT3/GPX4-dependent ferroptosis, providing mechanistic insights into the regulation of ferroptosis in gastric cancer.

Source: Current Issues in Molecular Biology

DOI: 10.3390/cimb48030300