Yang Min, Cui Weiwei, Lv Xiaoting, Xiong Gaozhong, Sun Caiyu, Xuan Haocheng, Ma Wei, Cui Xiuling, Cheng Yeping, Han Lihui, Chu Bo
Department of Immunology, Shandong Provincial Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, China.
Nat Commun. 2025 Jan 8;16(1):509. doi: 10.1038/s41467-024-55785-8.
Ferroptosis is a newly identified programmed cell death induced by iron-driven lipid peroxidation and implicated as a potential approach for tumor treatment. However, emerging evidence indicates that hepatocellular carcinoma (HCC) cells are generally resistant to ferroptosis and the underlying molecular mechanism is poorly understood. Here, our study confirms that S100 calcium binding protein P (S100P), which is significantly up-regulated in ferroptosis-resistant HCC cells, efficiently inhibits ferroptosis. Mechanistically, S100P facilitates lysosomal degradation of acetyl-CoA carboxylase alpha (ACC1), which is indispensable for de novo biosynthesis of lipids. Loss of S100P elevates the expression of ACC1 and promotes ferroptotic sensitivity of HCC cells. S100P-mediated ACC1 degradation relies on RAB5C, which directs ACC1 to lysosome via P62-dependent selective autophagy. Knockdown of RAB5C or P62 abrogates S100P-induced lysosomal degradation of ACC1 and restores resistance of HCC cells to ferroptosis. Our work reveals an alternative anti-ferroptosis pathway and suggests S100P as a promising druggable target for ferroptosis-related therapy of HCC.
铁死亡是一种新发现的由铁驱动的脂质过氧化诱导的程序性细胞死亡，被认为是一种潜在的肿瘤治疗方法。然而，新出现的证据表明，肝细胞癌（HCC）细胞通常对铁死亡具有抗性，其潜在的分子机制尚不清楚。在此，我们的研究证实，在抗铁死亡的HCC细胞中显著上调的S100钙结合蛋白P（S100P）能有效抑制铁死亡。从机制上讲，S100P促进乙酰辅酶A羧化酶α（ACC1）的溶酶体降解，而ACC1是脂质从头生物合成所必需的。S100P的缺失会提高ACC1的表达，并促进HCC细胞对铁死亡的敏感性。S100P介导的ACC1降解依赖于RAB5C，RAB5C通过依赖于P62的选择性自噬将ACC1导向溶酶体。敲低RAB5C或P62可消除S100P诱导的ACC1溶酶体降解，并恢复HCC细胞对铁死亡的抗性。我们的工作揭示了一种替代性的抗铁死亡途径，并表明S100P是HCC铁死亡相关治疗的一个有前景的可成药靶点。
