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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月23日

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  • Xiao Zhang,
  • Shurui Cao,
  • Chenchen Zhou,
  • Wen Jiang,
  • Hongshun Wang,
  • Bingqing Hui,
  • Xiaheng Deng,
  • Yanhong Gu

摘要

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.