ACSM5 Regulates Ferroptosis in Hepatocellular Carcinoma - by Up-Regulating POR and Modulating Lipid Metabolism

Sep 23, 2026

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The study investigates how medium-chain fatty acyl-CoA synthetase-5 (ACSM5) influences hepatocellular carcinoma progression through ferroptosis. Overexpression of ACSM5 markedly suppresses proliferation of LM3 and HepG2 cells, an effect blocked by the ferroptosis inhibitor deferoxamine. ACSM5 increases malondialdehyde and lipid reactive oxygen species while decreasing glutathione, thereby triggering ferroptosis. Mechanistically, ACSM5 promotes upregulation of cytochrome P450 oxidoreductase (POR), and POR knockdown prevents ACSM5-driven ferroptosis. ACSM5 also enhances arachidonic acid generation, increasing ferroptosis sensitivity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

ACSM5 and liver cancer background

Ferroptosis as an iron-dependent lipid peroxidation process

Mechanistic rationale

Lipid metabolism and ROS/iron regulation in tumors

POR and polyunsaturated fatty acid-driven ferroptosis

Conclusions (from abstract)

Cancer Science ORIGINAL ARTICLE OPEN ACCESS ACSM5 Regulates Ferroptosis in Hepatocellular Carcinoma by Up-Regulating POR and Modulating Lipid Metabolism Zhengqiang Wu | Xiaofeng Xiong | Mingyi Dong | Linfei Luo | Zixiang Huang | Kedong Xu | Lianwu Zhao | Fenfen Wang | Zhili Wen Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Correspondence: Fenfen Wang ([553266419@qq.com](553266419@qq.com)) | Zhili Wen ([wenzhili1@163.com](wenzhili1@163.com)) Received: 23 January 2025 | Revised: 21 May 2025 | Accepted: 25 May 2025 Funding: This work was supported by National Natural Science Foundation of China, 81960440, 82070594. Keywords: ACSM5 | ferroptosis | hepatocellular carcinoma | lipid metabolism | lipid peroxidation | POR ABSTRACT 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. 1 | Introduction Hepatocellular carcinoma, a type of tumor with a high degree of malignancy, has a relatively high incidence and mortality rate worldwide and constitutes a significant threat to public health [1] . The pathogenesis of hepatocellular carcinoma is complex [2] . Various liver-infecting viruses, parasites, and toxins can damage the liver. Moreover, they activate intracellular pathways and kinases in hepatocytes, resulting in liver injury and the occurrence of liver cancer. Furthermore, the occurrence and development of hepatocellular carcinoma involve the regulation of multiple genes, multiple stages, and multiple steps [3] . Thus, clarifying the molecular mechanism underlying the occurrence of liver cancer is highly important for identifying effective molecular therapeutic targets. Ferroptosis is a unique form of cell death discovered in recent years that is driven by iron-dependent lipid peroxidation. Its main feature is the lethal accumulation of intracellular lipid peroxides, which damage cell membranes, proteins, and DNA, thereby leading to cell death [4] . Ferroptosis in cells involves three biological processes: lipid metabolism, the participation of ROS, and iron regulation. Any biological activity within cells that is involved in regulating the aforementioned | Abbreviations: ACSL4, long-chain fatty acid-CoA ligase 4; ACSM5, medium-chain fatty acyl-CoA synthetase-5; ARA, arachidonic acid; COA, coenzyme A; GSH, glutathione; LPCAT3, lysophosphatidylcholine acyltransferase 3; LPOs, lipid peroxides; MDA, malondialdehyde; POR, cytochrome P450 oxidoreductase; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; RSD, relative standard deviation; VIP, variable importance in the projection.
Zhengqiang Wu, Xiaofeng Xiong and Mingyi Dong contributed equally. | | --- | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

FAQs

How does ACSM5 affect hepatocellular carcinoma cells in this study?

ACSM5 overexpression significantly inhibits proliferation of LM3 and HepG2 cells. The inhibition is prevented by the ferroptosis inhibitor deferoxamine, indicating a ferroptosis-related mechanism.

What biochemical changes indicate that ferroptosis is triggered by ACSM5?

ACSM5 increases malondialdehyde (MDA) and lipid reactive oxygen species (ROS) levels while reducing glutathione (GSH). These changes support ferroptosis activation via lipid peroxidation.

Why is POR important for ACSM5-induced ferroptosis?

ACSM5 promotes upregulation of cytochrome P450 oxidoreductase (POR). Knocking down POR blocks the enhancing effect of ACSM5 on ferroptosis in hepatocellular carcinoma.

Sep 23, 2026

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