Chen Yiling, Lee Derek, Kwan Kenneth Kin-Leung, Wu Mengjie, Wang Gengchao, Zhang Misty Shuo, Deng Haijing, Cheu Jacinth Wing-Sum, Lau Mandy Ho-Ying, Chan Cerise Yuen-Ki, Ooi Zher Yee, Wu Yibing, Bao Macus Hao-Ran, Lo Regina Cheuk-Lam, Ng Irene Oi-Lin, Wong Chun-Ming, Wong Carmen Chak-Lui
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China.
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
J Hepatol. 2025 Jul 11. doi: 10.1016/j.jhep.2025.06.034.
BACKGROUND & AIMS: Ferroptosis has emerged as a promising therapeutic approach for hepatocellular carcinoma (HCC). To evade ferroptosis, HCC cells depend on the glutathione/GPX4 and CoQ10/FSP1 antioxidant systems. The mevalonate pathway enzyme mevalonate diphosphate decarboxylase (MVD) generates isopentenyl pyrophosphate (IPP), which supports both selenocysteine-tRNA modification and CoQ10 biosynthesis. Here, we investigated the role of the mevalonate pathway in HCC and explored novel vulnerabilities for therapeutic targeting.
The clinical relevance of MVD expression was assessed in human HCC samples. Regulation of MVD was examined using chromatin immunoprecipitation. Targeted metabolomics was performed to measure IPP and CoQ10 levels. Selenoprotein translation was evaluated via ribosome and polysome profiling. Multiple in vitro and in vivo HCC models were used to assess the efficacy of mevalonate pathway inhibitors.
MVD was significantly overexpressed in human HCC tissues. Pharmacological inhibition of MVD using 6-FMEV reduced levels of IPP and CoQ10, suppressed selenoprotein translation, and triggered ferroptosis in HCC cells. Genetic ablation of TRSP (which encodes selenocysteine-tRNA) or TRIT1 (responsible for iA tRNA modification) similarly blocked selenoprotein synthesis and induced ferroptosis. In mouse models, both 6-FMEV and atorvastatin (a clinically approved upstream mevalonate pathway inhibitor) effectively suppressed HCC tumor growth, including steatotic HCC. Moreover, mevalonate pathway inhibition showed synergistic anti-tumor effects when combined with either tyrosine kinase inhibitors or anti-PD-1 immunotherapy.
Our findings reveal a critical link between the mevalonate pathway, CoQ10 production, and selenoprotein translation in protecting HCC cells from ferroptosis. The demonstrated anti-tumor role of 6-FMEV and atorvastatin supports the therapeutic potential of targeting the mevalonate pathway in HCC, either alone or in combination with existing treatments.
Current therapies show limited efficacy for advanced hepatocellular carcinoma (HCC). This study demonstrates that targeting the mevalonate pathway induces ferroptosis in HCC by disrupting CoQ10 biosynthesis and selenoprotein translation. Clinically relevant inhibitors, such as atorvastatin and the MVD inhibitor 6-FMEV, effectively suppressed tumor growth across multiple HCC subtypes in preclinical models. Furthermore, combining mevalonate pathway inhibitors with tyrosine kinase inhibitors or immune checkpoint inhibitors enhanced anti-tumor efficacy. These findings underscore the translational potential of mevalonate pathway inhibition as a novel therapeutic strategy for HCC.
铁死亡已成为一种有前景的肝细胞癌（HCC）治疗方法。为逃避铁死亡，HCC细胞依赖谷胱甘肽/GPX4和辅酶Q10/FSP1抗氧化系统。甲羟戊酸途径酶甲羟戊酸二磷酸脱羧酶（MVD）生成异戊烯基焦磷酸（IPP），其支持硒代半胱氨酸-tRNA修饰和辅酶Q10生物合成。在此，我们研究了甲羟戊酸途径在HCC中的作用，并探索了治疗靶点的新弱点。
在人HCC样本中评估MVD表达的临床相关性。使用染色质免疫沉淀法检测MVD的调控。进行靶向代谢组学以测量IPP和辅酶Q10水平。通过核糖体和多核糖体分析评估硒蛋白翻译。使用多种体外和体内HCC模型评估甲羟戊酸途径抑制剂的疗效。
MVD在人HCC组织中显著过表达。使用6-FMEV对MVD进行药理学抑制可降低IPP和辅酶Q10水平，抑制硒蛋白翻译，并在HCC细胞中引发铁死亡。TRSP（编码硒代半胱氨酸-tRNA）或TRIT1（负责iA tRNA修饰）的基因敲除同样阻断了硒蛋白合成并诱导了铁死亡。在小鼠模型中，6-FMEV和阿托伐他汀（一种临床批准的上游甲羟戊酸途径抑制剂）均有效抑制HCC肿瘤生长，包括脂肪变性HCC。此外，甲羟戊酸途径抑制与酪氨酸激酶抑制剂或抗PD-1免疫疗法联合使用时显示出协同抗肿瘤作用。
我们的研究结果揭示了甲羟戊酸途径、辅酶Q10产生和硒蛋白翻译之间在保护HCC细胞免受铁死亡方面的关键联系。6-FMEV和阿托伐他汀所显示的抗肿瘤作用支持了靶向甲羟戊酸途径在HCC中单独或与现有治疗联合使用的治疗潜力。
目前的疗法对晚期肝细胞癌（HCC）疗效有限。本研究表明，靶向甲羟戊酸途径通过破坏辅酶Q10生物合成和硒蛋白翻译在HCC中诱导铁死亡。临床相关抑制剂，如阿托伐他汀和MVD抑制剂6-FMEV，在临床前模型中有效抑制了多种HCC亚型的肿瘤生长。此外，将甲羟戊酸途径抑制剂与酪氨酸激酶抑制剂或免疫检查点抑制剂联合使用可增强抗肿瘤疗效。这些发现强调了甲羟戊酸途径抑制作为HCC新型治疗策略的转化潜力。
