Li Xinmiao, Li Yifei, Zhang Weizhi, Jiang Feng, Lin Lifan, Wang Yining, Wu Lingling, Zeng Han, Zheng Jianjian
Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
School of Mental Health, Wenzhou Medical University, Wenzhou, China.
Clin Transl Med. 2024 Aug;14(8):e1793. doi: 10.1002/ctm2.1793.
Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications.
N-methyladenosine (mA), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader gene mediating mA modifications, in liver fibrosis remains unclear.
This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi-omics analysis revealed that HSC-specific IGF2BP3 knockout decreased mA content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split-1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%-62% and protein levels to 28%-35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%-38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression.
These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis.
KEY POINTS/HIGHLIGHTS: IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated mA modifications promote HSC ferroptosis. IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis. IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis.
肝纤维化主要由肝星状细胞（HSC）的激活驱动，这涉及多种表观遗传修饰。
N-甲基腺苷（mA）是真核细胞中最普遍的RNA修饰，影响众多生理和病理过程。然而，作为介导mA修饰的读取基因，胰岛素样生长因子2 mRNA结合蛋白3（IGF2BP3）在肝纤维化中的作用仍不清楚。
本研究表明，IGF2BP3基因敲除通过促进HSC铁死亡（FPT）和使HSC失活来减轻肝纤维化。多组学分析显示，HSC特异性IGF2BP3基因敲除降低了Notch信号通路关键成分锯齿状蛋白1（Jag1）中的mA含量。此外，IGF2BP3缺乏显著降低了Notch/Jag1信号通路中的转录因子毛状分裂增强子1（Hes1）的表达，mRNA水平降至35%-62%，蛋白质水平降至28%-35%。此外，它抑制了FPT的负调节因子谷胱甘肽过氧化物酶4（GPX4）（降至约31%-38%），从而促进HSC FPT进程并降低促纤维化基因表达。
这些发现揭示了一条涉及HSC FPT的新型IGF2BP3/Notch/Jag1信号通路，为改善肝纤维化提供了有前景的靶点。
要点/亮点：IGF2BP3缺乏使Jag1信号失活。IGF2BP3缺乏介导的mA修饰促进HSC铁死亡。IGF2BP抑制通过Hes1/GPX4轴促进HSC铁死亡。IGF2BP3缺乏使Jag1/Notch1/3/Hes1信号通路失活，导致GPX4减少，这有助于HSC铁死亡。
