Niu Yan, Liu Chunyu, Jia Lizhou, Zhao Fangxin, Wang Yixiao, Wang Lu, Chen Weiyi, Gan Yanzi, Wen Yongjun
College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, People's Republic of China.
College of Basic Medicine, Inner Mongolia Medical University, Hohhot, China.
Hum Cell. 2025 Mar 8;38(3):66. doi: 10.1007/s13577-025-01195-x.
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.
胃癌是全球癌症相关死亡的主要原因之一，而化疗耐药性仍然是有效治疗的主要障碍。铁死亡是一种新型的程序性细胞死亡形式，已成为治疗癌症的一种潜在治疗策略。然而，胃癌中铁死亡的分子调控机制仍 largely unknown。在本研究中，我们鉴定出 syntaxin 1A（STX1A）是胃癌中线粒体功能和铁死亡的新型调节因子。我们发现 STX1A 在胃癌细胞系和组织中过表达，其敲低可抑制细胞增殖并诱导铁死亡。值得注意的是，我们有了一个新发现，即 STX1A 定位于线粒体，这在 STX1A 和线粒体功能之间建立了直接联系。从机制上讲，我们证明 STX1A 的缺失会损害线粒体呼吸，导致氧化应激增加和铁死亡。此外，我们表明靶向 STX1A 或直接抑制线粒体功能可通过诱导铁死亡来逆转胃癌细胞对 5-氟尿嘧啶和顺铂的获得性耐药。我们的研究结果为胃癌中铁死亡的调控提供了新见解，并表明 STX1A-线粒体-铁死亡轴可能是克服化疗耐药性和改善患者预后的有前景的治疗靶点。
