Lin Guoliang, Liu Qingnan, Xie Chengjie, Ding Ke, Mo Guanghua, Zeng Lu, Zhang Fan, Liu RuiXuan, Lu Lei, Hong Wei, Mao Yuling, Su Haibo, Li Shuai
Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China.
GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, PR China.
Cell Commun Signal. 2025 Mar 12;23(1):132. doi: 10.1186/s12964-025-02126-x.
To successfully metastasize, cancer cells must evade detachment induced cell death, known as anoikis. Unraveling the mechanisms that gastric cancer (GC) circumvent anoikis and achieve peritoneal metastasis especially during unanchored growth, could significantly improve patient outcomes. Our study reveals that GC cells exhibit increased lipid peroxidation, MDA production, and cell death during suspension culture, which can be mitigated by the intervention with liproxstatin-1 and ferrostatin-1. We discovered that oleic acid (OA) or adipocytes stimulate lipid accumulation in GC cells, thereby inhibiting lipid peroxidation and cell death. Lipid mass spectrometry confirmed an upregulation of triglyceride synthesis, indicating that the accumulation of lipid droplet may confer resistance to ferroptosis during suspension growth. In vitro assays demonstrated that OA not only induces lipid droplet accumulation but also upregulates the expression of ferroptosis suppressor protein 1 (FSP1), a process that can be abrogated by the double knockout of GPD1/1L genes. Additionally, we have demonstrated that a decrease in the ubiquitination of FSP1 in GC cells upon lipid droplet accumulation, as well as silencing or pharmacological targeting FSP1, promotes ferroptosis and disrupts the peritoneal metastatic potential of GC cells. Collectively, our findings highlight the potential of FSP1 as a promising therapeutic target for metastatic gastric cancer.
为了成功转移，癌细胞必须逃避因脱离而引发的细胞死亡，即失巢凋亡。阐明胃癌（GC）规避失巢凋亡并实现腹膜转移的机制，尤其是在无锚定生长期间，可能会显著改善患者的预后。我们的研究表明，GC细胞在悬浮培养期间表现出脂质过氧化增加、丙二醛（MDA）生成增加和细胞死亡，而脂氧素A1（liproxstatin-1）和铁死亡抑制蛋白1（ferrostatin-1）的干预可以减轻这些现象。我们发现油酸（OA）或脂肪细胞会刺激GC细胞中的脂质积累，从而抑制脂质过氧化和细胞死亡。脂质质谱分析证实甘油三酯合成上调，表明脂滴的积累可能在悬浮生长期间赋予对铁死亡的抗性。体外试验表明，OA不仅诱导脂滴积累，还上调铁死亡抑制蛋白1（FSP1）的表达，这一过程可被GPD1/1L基因的双敲除所消除。此外，我们已经证明，GC细胞中脂滴积累时FSP1的泛素化减少，以及FSP1的沉默或药物靶向作用，都会促进铁死亡并破坏GC细胞的腹膜转移潜能。总的来说，我们的研究结果突出了FSP1作为转移性胃癌有前景的治疗靶点的潜力。
