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Abstract：
BACKGROUND: Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications.
OBJECTIVE: N6-methyladenosine (m6A), 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 m6A modifications, in liver fibrosis remains unclear.
RESULTS: 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 m6A 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.
CONCLUSIONS: These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis.
UNASSIGNED: IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated m6A 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.
OBJECTIVE: N6-methyladenosine (m6A), 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 m6A modifications, in liver fibrosis remains unclear.
RESULTS: 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 m6A 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.
CONCLUSIONS: These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis.
UNASSIGNED: IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated m6A 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.
摘要：
背景：肝纤维化主要由肝星状细胞（HSC）的激活驱动，其中涉及各种表观遗传修饰。
目标：N6-甲基腺苷（m6A），真核细胞中最普遍的RNA修饰，影响许多生理和病理过程。然而，胰岛素样生长因子2mRNA结合蛋白3（IGF2BP3）的作用，介导m6A修饰的阅读器基因，肝纤维化仍不清楚。
结果：这项研究表明，IGF2BP3敲除通过促进HSC铁凋亡（FPT）和灭活HSC来减少肝纤维化。多组学分析显示，HSC特异性IGF2BP3敲除降低了Jagged1（Jag1）中的m6A含量，Notch信号通路的关键组成部分。此外，IGF2BP3缺乏显著降低了split-1(Hes1)的毛状和增强子的表达,Notch/Jag1信号通路中的转录因子，mRNA水平下降到35%-62%，蛋白质水平下降到28%-35%。此外,它抑制了谷胱甘肽过氧化物酶4（GPX4）（降低至约31％-38％），FPT的负调节器，从而促进HSCFPT进展并减少促纤维化基因表达。
结论：这些发现揭示了涉及HSCFPT的新型IGF2BP3/Notch/Jag1信号通路，提示改善肝纤维化的有希望的目标。
■IGF2BP3缺乏症使Jag1信号失活。IGF2BP3缺陷介导的m6A修饰促进HSC铁凋亡。IGF2BP3抑制通过Hes1/GPX4轴促进HSC中的铁凋亡。IGF2BP3缺乏使Jag1/Notch1/3/Hes1信号通路失活,导致GPX4的减少，这有助于HSC铁凋亡。
目标：N6-甲基腺苷（m6A），真核细胞中最普遍的RNA修饰，影响许多生理和病理过程。然而，胰岛素样生长因子2mRNA结合蛋白3（IGF2BP3）的作用，介导m6A修饰的阅读器基因，肝纤维化仍不清楚。
结果：这项研究表明，IGF2BP3敲除通过促进HSC铁凋亡（FPT）和灭活HSC来减少肝纤维化。多组学分析显示，HSC特异性IGF2BP3敲除降低了Jagged1（Jag1）中的m6A含量，Notch信号通路的关键组成部分。此外，IGF2BP3缺乏显著降低了split-1(Hes1)的毛状和增强子的表达,Notch/Jag1信号通路中的转录因子，mRNA水平下降到35%-62%，蛋白质水平下降到28%-35%。此外,它抑制了谷胱甘肽过氧化物酶4（GPX4）（降低至约31％-38％），FPT的负调节器，从而促进HSCFPT进展并减少促纤维化基因表达。
结论：这些发现揭示了涉及HSCFPT的新型IGF2BP3/Notch/Jag1信号通路，提示改善肝纤维化的有希望的目标。
■IGF2BP3缺乏症使Jag1信号失活。IGF2BP3缺陷介导的m6A修饰促进HSC铁凋亡。IGF2BP3抑制通过Hes1/GPX4轴促进HSC中的铁凋亡。IGF2BP3缺乏使Jag1/Notch1/3/Hes1信号通路失活,导致GPX4的减少，这有助于HSC铁凋亡。
