Wu Zhengqiang, Xiong Xiaofeng, Dong Mingyi, Luo Linfei, Huang Zixiang, Xu Kedong, Zhao Lianwu, Wang Fenfen, Wen Zhili
Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Cancer Sci. 2025 Aug;116(8):2125-2136. doi: 10.1111/cas.70115. Epub 2025 Jun 2.
The medium-chain fatty acyl-CoA synthetase-5 (ACSM5) plays a crucial role in the development of some cancers. However, its impact on liver cancer is still not clear. In this study, we found that the proliferation ability of LM3 and HepG2 cells was significantly inhibited after ACSM5 was overexpressed, and this change was blocked by the ferroptosis inhibitor deferoxamine. ACSM5 increased the levels of malondialdehyde (MDA) and lipid reactive oxygen species (ROS), reduced the level of glutathione (GSH), and thus triggered ferroptosis. Furthermore, ACSM5 promoted the upregulation of cytochrome P450 oxidoreductase (POR). Knocking down POR blocked the promoting effect of ACSM5 on ferroptosis in HCC. Moreover, ACSM5 promoted the generation of arachidonic acid and thus increased the sensitivity to ferroptosis. In summary, our findings indicate that ACSM5 induces ferroptosis in hepatocellular carcinoma (HCC) by upregulating POR. The metabolic transformation of linoleic acid to arachidonic acid was also promoted by ACSM5; therefore, sensitivity to ferroptosis was increased.
中链脂肪酰辅酶A合成酶5（ACSM5）在某些癌症的发展中起着关键作用。然而，其对肝癌的影响仍不清楚。在本研究中，我们发现ACSM5过表达后，LM3和HepG2细胞的增殖能力显著受到抑制，且这种变化被铁死亡抑制剂去铁胺阻断。ACSM5增加了丙二醛（MDA）和脂质活性氧（ROS）的水平，降低了谷胱甘肽（GSH）的水平，从而引发铁死亡。此外，ACSM5促进了细胞色素P450氧化还原酶（POR）的上调。敲低POR可阻断ACSM5对肝癌铁死亡的促进作用。此外，ACSM5促进了花生四烯酸的生成，从而增加了对铁死亡的敏感性。总之，我们的研究结果表明，ACSM5通过上调POR诱导肝癌（HCC）中的铁死亡。ACSM5还促进了亚油酸向花生四烯酸的代谢转化；因此，增加了对铁死亡的敏感性。
