Yu Heng-Chao, Jin Liang, Bai Lu, Zhang Yu-Jia, Yang Zhao-Xu
Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China.
Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, China.
Cell Death Discov. 2025 Apr 16;11(1):178. doi: 10.1038/s41420-025-02480-2.
Altered lipid metabolism is an emerging hallmark of cancer, which is involved in various aspects of the cancer phenotypes. C12ORF49 has recently been identified as a pivotal regulator of sterol regulatory element binding proteins (SREBPs), a family of transcriptional factors that govern lipid biosynthesis. Nevertheless, the function of C12ORF49 in human cancers has not been studied. Here, we show that C12ORF49 levels are higher in HCC tissue than in nearby non-cancerous liver tissue. Additionally, increased C12ORF49 expression is linked to poorer survival outcomes in HCC patients. Functional experiments uncovered that knockdown of C12ORF49 inhibited HCC cell survival and tumor growth by inducing ferroptosis, whereas the opposites were observed upon C12ORF49 overexpression. Mechanistically, C12ORF49 promotes SREBP1/SCD-regulated production of monounsaturated fatty acids, which inhibits ferroptosis in HCC cells. Furthermore, silencing C12ORF49 combined with Sorafenib treatment showed a synergistic effect in inducing HCC cell death. Together, our findings suggest a critical role of C12ORF49 in the evasion of ferroptosis in HCC cells, highlighting the potential of targeting C12ORF49 as a therapeutic strategy to enhance the efficacy of Sorafenib treatment in HCC.
脂质代谢改变是癌症新出现的一个标志，它涉及癌症表型的各个方面。C12ORF49最近被确定为固醇调节元件结合蛋白（SREBPs）的关键调节因子，SREBPs是一类控制脂质生物合成的转录因子。然而，C12ORF49在人类癌症中的功能尚未得到研究。在此，我们表明，肝癌组织中C12ORF49的水平高于附近的非癌性肝组织。此外，C12ORF49表达增加与肝癌患者较差的生存结果相关。功能实验发现，敲低C12ORF49可通过诱导铁死亡抑制肝癌细胞存活和肿瘤生长，而C12ORF49过表达时则观察到相反的结果。机制上，C12ORF49促进SREBP1/SCD调节的单不饱和脂肪酸生成，从而抑制肝癌细胞中的铁死亡。此外，沉默C12ORF49与索拉非尼治疗联合使用在诱导肝癌细胞死亡方面显示出协同效应。总之，我们的研究结果表明C12ORF49在肝癌细胞逃避铁死亡中起关键作用，突出了将靶向C12ORF49作为一种治疗策略以提高索拉非尼治疗肝癌疗效的潜力。
