肝癌细胞 z-bio 2025-07-24 4043

　　On July 11, 2025, the team of Huang Zelei of the University of Hong Kong published a research paper entitled "Mevalonate pathway promotes liver cancer by suppressing ferroptosis through CoQ10 production and selenocysteine-tRNA modification" in Journal of Hepatology (IF=33).

　　The study revealed that the mevalonate pathway inhibits iron death by generating coenzyme Q10 (CoQ10) and regulating selenocysteine-tRNA modification, thereby promoting the development of liver cancer. This discovery also provides a new target for liver cancer treatment.

　　As a new cell death method, ferrodystrophy has been considered a potential new direction for liver cancer treatment. Hepatocellular carcinoma cells rely on the two systems of glutathione/GPX4 and CoQ10/FSP1 to resist ferrodysfunction, while MVD, a key enzyme in the mevalonate pathway, can simultaneously regulate the production of CoQ10 and the modification of selenocysteine-tRNA, thereby affecting the function of these two anti-ferrodysfunction systems by generating metabolites IPP.

　　The research team found that the mevalonate pathway is abnormally activated in liver cancer (such as high MVD expression), and this pathway directly participates in the resistance of liver cancer cells to iron death by affecting CoQ10 synthesis and selenoprotein (such as GPX4) translation.

　　Therefore, the research team focused on the relationship between ferrous death and liver cancer, and then revealed the mechanism of action of the mevalonate pathway, providing a theoretical basis for targeted therapy.

　　Core mechanism: The dual carcinogenic effect of mevalonate pathway

　　The mevalonate pathway plays a dual role through the key enzyme MVD (mevalonate diphosphate decarboxylase):

　　● Catalytic generation of IPP: MVD converts mevalonate diphosphate (MVAPP) into isoprene pyrophosphate (IPP). IPP is not only a precursor for the synthesis of CoQ10 and a key raw material for selenocysteine-tRNA modification. CoQ10 directly inhibits iron death by reducing lipid peroxides.

　　● Dual anti-ferrode mortality effect: On the one hand, IPP promotes the production of CoQ10 and enhances the lipid peroxide scavenging ability; on the other hand, it catalyzes the formation of i⁶A₃₇ modification through TRIT1 enzyme to ensure the translation efficiency of selenoproteins such as GPX4.

　　When MVD function is inhibited, the reduction of IPP generation will simultaneously lead to a decrease in CoQ10 levels and GPX4 translation disorders, which doublely weakens the anti-ferrodysfunction ability of liver cancer cells, ultimately induces ferrodysfunction and inhibits tumor progression.

　　Verification of key experimental results

　　Clinical sample analysis showed that the MVD expression in tumor tissues of 62.7% of liver cancer patients was more than 2 times higher than that of normal tissues, and the high MVD expression was significantly correlated with the adverse prognosis of the patients (confirmed by the TCGA database and the Mary Hospital cohort in Hong Kong). Spatial transcriptome technology further confirmed that the mevalonate pathway is specifically activated in liver cancer tissues.

　　Through cell experiments and animal models, it was found that after knockdown or knockdown of MVD, the decrease in IPP level directly leads to a decrease in CoQ10 synthesis. At the same time, the hindered modification of i6A37 makes Sec-tRNA unstable, resulting in inhibition of selenoproteins such as GPX4 and TXNRD1.

　　The ribosome map shows that MVD deletion causes ribosomes to stagnate at the UGA codon (selenocysteine insertion site) of GPX4, further confirming the existence of translation obstacles.

　　In addition, knockout of TRSP (encoding Sec-tRNA) or TRIT1 (catalytic i6A modification) can directly block selenoprotein translation, induce ferrous death and significantly inhibit tumor growth and lung metastasis.

　　Exploration of treatment strategies

　　MVD inhibitor 6-FMEV can reduce CoQ10 levels and hinder selenoprotein translation by competitively inhibiting MVD activity. In in situ, subcutaneous and steatinized liver cancer models, iron death can be effectively induced and tumor growth can be inhibited. Even drug-resistant backgrounds such as TP53 mutation or NRF2 over-activation will not affect its effect.

　　Statins such as atorvastatin inhibit HMGCR, the upstream enzyme of mevalonate pathway, produce similar effects to 6-FMEV, and synergistically with existing therapies.

　　In addition, the combination of 6-FMEV or statins with TKI (such as lenvatinib) can enhance the ferrodysemia induction effect and overcome TKI resistance, while statins combined with anti-PD1 immunotherapy can significantly inhibit steatinized liver cancer and improve immunotherapy response.

　　This study provides multiple potential strategies for liver cancer treatment:

　　Targeted MVD: The MVD inhibitor 6-FMEV is highly specific and can avoid side effects such as myotoxicity of statins. It is suitable for refractory liver cancer (including steatosis subtypes).

　　New use of old drugs: Statins are low in cost and widely used in clinical practice. The combination of their combination with TKI or ICIs is easy to quickly convert into clinical treatment.

　　Biomarker guidance: The expression levels of MVD or GPX4 can be used as biomarkers to screen patients who are most likely to benefit from targeted treatment of mevalonate pathway to achieve individualized treatment.

　　In the future, the mevalonate pathway is expected to become a key target for liver cancer treatment and promote the innovation of liver cancer treatment models.