What question did this study set out to answer?

The study aims to elucidate the role of PTDSS1 in regulating glutathione synthesis and its impact on ferroptosis and mitophagy in ESCC cells.

April 25, 2026Open Access

Targeting PTDSS1 to modulate GSH synthesis triggers mitophagy and induces ferroptosis in esophageal squamous cell carcinoma cells

Key Points

The study aims to elucidate the role of PTDSS1 in regulating glutathione synthesis and its impact on ferroptosis and mitophagy in ESCC cells.
Single-cell RNA sequencing (scRNA-seq) analysis to identify PTDSS1-high malignant subpopulations.
PTDSS1 knockdown experiments to evaluate effects on SLC3A2 expression and GSH synthesis.
Investigation of mitophagy mechanisms through PINK1/Parkin pathway activation.
PTDSS1 knockdown led to decreased SLC3A2 expression, reduced GSH synthesis, and increased oxidative stress.
Activation of PINK1/Parkin pathway was confirmed, inducing both apoptosis and ferroptosis.
Increased PS levels and MFN2 translocation were observed, which facilitated mitophagy.

Abstract

Abstract PTDSS1 is an emerging oncogenic protein associated with poor survival rates across various cancer types, including esophageal squamous cell carcinoma (ESCC). However, its regulatory mechanisms and therapeutic potential in ESCC remain incompletely understood. Through single-cell RNA sequencing (scRNA-seq) analysis, we identified a PTDSS1-high malignant epithelial subpopulation characterized by resistance to ferroptosis and mitophagy. Our investigations demonstrated that PTDSS1 regulates glutathione (GSH) synthesis and coordinates mitophagy in ESCC cells. Mechanistically, PTDSS1 knockdown promotes interaction between TRIM21 and SLC3A2, leading to diminished SLC3A2 protein expression and subsequent reduction in GSH synthesis. This elevates cellular oxidative stress, thereby triggering PINK1/Parkin mitophagy pathway and ultimately inducing apoptosis and ferroptosis. Furthermore, at the mitochondrial level, the knockdown of PTDSS1 decreases phosphatidylserine (PS) and facilitates mitochondrial fusion protein 2 (MFN2) translocation, providing substrates for mitophagy. Collectively, our findings elucidate a novel mechanism by which PTDSS1 protects ESCC cells from death and offer new perspectives for therapeutic strategies that target PTDSS1 to induce mitophagy and ferroptosis in ESCC.

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