STX1A regulates ferroptosis and chemoresistance in gastric cancer through mitochondrial function modulation.

Abstract

Gastric cancer is one of the leading causes of cancer-related deaths worldwide, and chemoresistance remains a major obstacle to effective treatment. Ferroptosis, a novel form of regulated cell death, has emerged as a potential therapeutic strategy to treat cancer. However, the molecular mechanisms regulating ferroptosis in gastric cancer remain largely unknown. In this study, we identified syntaxin 1A (STX1A) as a novel regulator of mitochondrial function and ferroptosis in gastric cancer. We found that STX1A is overexpressed in gastric cancer cell lines and tissues and that its knockdown inhibits cell proliferation and induces ferroptosis. Notably, we made the novel discovery that STX1A is localized to the mitochondria, providing a direct link between STX1A and mitochondrial function. Mechanistically, we demonstrated that STX1A depletion impairs mitochondrial respiration, leading to increased oxidative stress and ferroptosis. Furthermore, we showed that targeting STX1A or directly inhibiting mitochondrial function can reverse acquired resistance to 5-fluorouracil and cisplatin in gastric cancer cells by inducing ferroptosis. Our findings provide new insights into the regulation of ferroptosis in gastric cancer and suggest that the STX1A-mitochondria-ferroptosis axis may be a promising therapeutic target for overcoming chemoresistance and improving patient outcomes.