The prognostic role of ACSL4 in postoperative adjuvant TACE-treated HCC: implications for therapeutic response and mechanistic insights

作者：Feng Ji, Jin-Lian Bin, Xiwen Liao, Yong Wu, Yue Tang, Peizhi Lu, Guangzhi Zhu, Qian-Ru Cui, Yock Young Dan, Guo‐Huan Yang, Lixin Li, Jing-Huan Deng, Tao Peng, Shing Chuan Hooi, Jing Zhou, Guo‐Dong Lu · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2024 · DOI：10.1186/s13046-024-03222-5 · 被引用次数：13 · 研究领域：Cancer, Lipids, and Metabolism、Peroxisome Proliferator-Activated Receptors、Cancer, Hypoxia, and Metabolism

Abstract Background The response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) treatment and its underlying mechanisms remain elusive. This study investigates the role of enzymes involved in fatty acid activation, specifically Acyl-CoA synthetase long chain 4 (ACSL4), in HCC patients treated with postoperative adjuvant TACE (PA-TACE) and in nutrient-deprived HCC cells. Methods We examined the expression of ACSL4 and its family members in HCC clinical samples and cell lines. The clinical significance of ACSL4, particularly regarding the prognosis of patients treated with PA-TACE, was assessed using two independent HCC cohorts. We further explored the role of ACSL4 in glucose starvation-induced cell death in HCC cells and xenograft mouse models. Results Among the family members, ACSL4 is the most up-regulated enzyme, associated with poor survival in HCC patients, particularly in post-recurrent TACE-treated patients in a Singapore cohort. ACSL4 is essential for HCC cell survival in response to glucose starvation, rather than to hypoxia or to the combination of hypoxia with doxorubicin or cisplatin. ACSL4-mediated arachidonic acid (AA) metabolism supports mitochondrial β -oxidation and energy production. CCAAT/enhancer binding protein α (CEBPA) transcriptionally regulates ACSL4 by binding 3 motifs (-623 to -613, -1197 to -1187 and -1745 to -1735) of ACSL4 upstream promoter region, enhancing its pro-survival effects. Furthermore, canagliflozin (Cana),...