Liang Yaxu, Yu Weiwei, Sun Haifeng, Wang Dayu, Wang Zhibo, Shi Hailing, Cao Yang, Zhang Zijie, Liu Jun, Zou Zhongyu, Wei Jiangbo, Wu Tong, Yu Dongming, Qi Jun, Wu Jiamin, Dickinson Bryan C, Zhu Pingping, Shen Bin, Sun Beicheng, He Chuan, Zhong Xiang
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, China.
Sci China Life Sci. 2025 May 30. doi: 10.1007/s11427-024-2793-x.
Liver injury is a major health issue with significant implications for liver function and overall well-being, but precise mechanisms of the N-methyladenine (mA) reader YTHDF3 in liver injury remain severely understudied. Here, we discovered that Ythdf3 knockout exacerbated CCL-induced liver injury with a reduction in functional hepatocytes and liver stem cells using single cell RNA-sequencing and organoid culture. Furthermore, Mettl14 and YTHDF3-dependent RNA mA dysregulation induced DNA damage. Moreover, we found YTHDF3 could bind and modulate CCAAT/enhancer-binding protein-alpha (CEBPA) translation in an mA-dependent manner. Mechanistically, knockout of Ythdf3 impeded the translation of CEBPA, subsequently inhibiting the expression of poly(ADP-ribose) (PAR) polymerase-1 (PARP1) and Peroxiredoxin 2 (PRDX2). This inhibition promoted DNA damage and genomic instability, ultimately exacerbating liver damage. This work uncovers an essential role of mA/YTHDF3/CEBPA regulatory axes in governing cell fates and genomic stability, thereby preventing liver injury. Importantly, these findings offer potential therapeutic avenues for targeting YTHDF3 and CEBPA in the treatment of liver injury-related diseases.
肝损伤是一个重大的健康问题，对肝功能和整体健康有着重大影响，但N-甲基腺嘌呤（mA）阅读器YTHDF3在肝损伤中的精确机制仍严重缺乏研究。在这里，我们发现，使用单细胞RNA测序和类器官培养，Ythdf3基因敲除加剧了CCL诱导的肝损伤，功能性肝细胞和肝干细胞减少。此外，Mettl14和YTHDF3依赖性RNA mA失调诱导DNA损伤。此外，我们发现YTHDF3可以以mA依赖的方式结合并调节CCAAT/增强子结合蛋白α（CEBPA）的翻译。从机制上讲，Ythdf3基因敲除阻碍了CEBPA的翻译，随后抑制了聚（ADP-核糖）（PAR）聚合酶-1（PARP1）和过氧化物酶2（PRDX2）的表达。这种抑制促进了DNA损伤和基因组不稳定，最终加剧了肝损伤。这项工作揭示了mA/YTHDF3/CEBPA调节轴在控制细胞命运和基因组稳定性方面的重要作用，从而预防肝损伤。重要的是，这些发现为靶向YTHDF3和CEBPA治疗肝损伤相关疾病提供了潜在的治疗途径。
