胃癌（GC）是世界上最常见的恶性肿瘤之一。作为铁死亡的核心调节器，GPx4已成为开发抗癌药物的潜在分子靶点。在本研究中，我们发现GPx4在胃癌中过度表达，并与恶性预后呈负相关，同时也与胃癌的发展有关。我们使用分子对接和基于结构的虚拟筛选进行筛选潜在的GPx4抑制剂，并鉴定出一种新型GPx4抑制剂polyphyllin B（PB），它可以通过下调胃癌细胞中的GPx4表达诱导铁死亡。在体外实验中，PB还被证明能够抑制细胞增殖、抑制侵袭和迁移、诱导凋亡并阻止胃癌细胞的细胞周期进程。然后，免疫荧光和Western印迹实验确认PB可以在体外调节LC3B、TFR1、NOCA4和FTH1的表达，提示PB可能通过TFR1将Fe3+转运到细胞中，并促进NCOA4依赖性的铁自噬来增加Fe2+的水平。此外，PB还可以通过在体内调节GPx4、TFR1、NOCA4和FTH1的表达来抑制胃癌的生长，从而在GC的同种移植模型中显示出良好的抗肿瘤效果。总之，我们确认GPx4可能是胃癌治疗的一个潜在靶点，PB可能是治疗胃癌的一种新型和有前途的药物，它通过诱导铁死亡在胃癌细胞和小鼠模型中显示良好的抗肿瘤效果，且不会产生显著的宿主毒性。©作者。

Gastric cancer (GC) is one of the most common malignant tumors in the world. GPx4, as the core regulator of ferroptosis, has become a potential molecular target for developing anticancer agents. In the present study, we found that GPx4 was overexpressed and negatively correlated with poor prognosis in GC, while it was associated with the GC development. Molecular docking and structure-based virtual screening assays were used to screen potential GPx4 inhibitors, and we identified a novel GPx4 inhibitor, polyphyllin B (PB), which can induce ferroptosis by down-regulating GPx4 expression in GC cells. It has also been shown to inhibit cell proliferation, suppress invasion and migration, induce apoptosis, and block the cell cycle progression in GC cells in vitro. Then, immunofluorescence and western blotting assay confirmed that PB can regulate the expression of LC3B, TFR1, NOCA4 and FTH1 in vitro, which suggested that suggest that PB may increase the level of Fe2+ by transporting Fe3+ into the cell by TFR1 and promoting NCOA4-dependent iron autophagy. In addition, PB can also suppresses tumor growth in an orthotopic mouse model of GC via regulating the expression of GPx4, TFR1, NOCA4 and FTH1 in vivo. In summary, we confirmed that GPx4 may be a potential target for GC treatment, PB may be a novel and promising drug for the treatment of GC, which shows good antitumor efficacy without causing significant host toxicity via inducing ferroptosis in both gastric cancer cells and mouse models.© The author(s).