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

## TL;DR

This study shows that a mitochondrial enzyme called PISD helps prevent ferroptosis in gastric cancer cells by maintaining phospholipid balance and supporting STAT3/GPX4 signaling.

## Contribution

The novel finding is that PISD regulates ferroptosis in gastric cancer through mitochondrial PE homeostasis and STAT3/GPX4 signaling.

## Key findings

- PISD downregulation increases ferroptosis in gastric cancer cells by reducing PE levels and impairing mitochondrial function.
- PISD depletion leads to reduced STAT3 phosphorylation and GPX4 expression, causing lipid peroxidation and iron accumulation.
- Inhibiting ferroptosis or supplementing with LPE can partially reverse PISD knockdown effects in gastric cancer models.

## 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.