Shi Chang'e, Yan Hezhong, Zhao Qihong, Dou Zhengli, Kong Dejie, Wang Wensheng
Department of Gastroenterology, Anhui Public Health Clinical Center, Hefei, China.
Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University North District, Hefei, China.
DNA Cell Biol. 2025 Apr 28. doi: 10.1089/dna.2025.0015.
Gastric cancer (GC) remains the leading cause of cancer deaths worldwide. GC development is a multistep and multifactorial process, and the molecular characterization of the multistage progression of gastric lesions to GC is poorly understood. Induction of ferroptosis driven by iron-dependent phospholipid peroxidation ameliorates the malignant progression of GC. Here, we found that solute carrier family 47 member 1 (SLC47A1) promoted GC progression by regulating ferroptosis. Clinically, SLC47A1 was elevated during the progression of gastritis to GC, and its high expression was associated with poor prognosis in patients with GC. Knockdown of SLC47A1 significantly inhibited cell proliferation, colony formation, and tumor growth. Further studies revealed that SLC47A1 was a regulator of ferroptosis rather than apoptosis or necrosis. Knockdown of SLC47A1 promoted ferroptosis in GC cells, as evidenced by increased erastin-induced cytoplasmic membrane rupture, cell death, lipid peroxidation, and malondialdehyde levels. Mechanistically, GATA6 promoted SLC47A1 transcription, leading to elevated SLC47A1 expression and promoting ferroptosis in GC cells. In summary, our study revealed the significant role of SLC47A1 in the development and progression of GC through regulating ferroptosis. Targeting the GATA6/SLC47A1 axis may be a promising therapeutic strategy for GC.
胃癌（GC）仍然是全球癌症死亡的主要原因。胃癌的发生是一个多步骤、多因素的过程，而胃病变向胃癌多阶段进展的分子特征尚不清楚。铁依赖性磷脂过氧化驱动的铁死亡诱导可改善胃癌的恶性进展。在这里，我们发现溶质载体家族47成员1（SLC47A1）通过调节铁死亡促进胃癌进展。临床上，SLC47A1在胃炎向胃癌进展过程中升高，其高表达与胃癌患者的不良预后相关。敲低SLC47A1可显著抑制细胞增殖、集落形成和肿瘤生长。进一步研究表明，SLC47A1是铁死亡的调节因子，而非凋亡或坏死的调节因子。敲低SLC47A1可促进胃癌细胞的铁死亡，这表现为埃拉斯汀诱导的细胞质膜破裂、细胞死亡、脂质过氧化和丙二醛水平增加。机制上，GATA6促进SLC47A1转录，导致SLC47A1表达升高，并促进胃癌细胞的铁死亡。总之，我们的研究揭示了SLC47A1通过调节铁死亡在胃癌发生和进展中的重要作用。靶向GATA6/SLC47A1轴可能是一种有前景的胃癌治疗策略。
