YTHDF1 shapes immune-mediated hepatitis via regulating inflammatory cell recruitment and response  

作　　者：Hao Li Kailun Yu Xiandan Zhang Jiawen Li Huilong Hu Xusheng Deng Siyu Zeng Xiaoning Dong Junru Zhao Yongyou Zhang 

机构地区：[1]State Key Laboratory of Cellular Stress Biology,Innovation Center for Cell Signaling Network,School of Life Sciences,Xiamen University,Xiamen,Fujian 361102,China [2]National Institute for Data Science in Health and Medicine Engineering,Faculty of Medicine and Life Sciences,Xiamen University,Xiamen,Fujian 361102,China [3]School of Pharmaceutical Sciences,Xiamen University,Xiamen,Fujian 361102,China

出　　处：《Genes & Diseases》2025年第3期550-566,共17页基因与疾病(英文)

基　　金：supported by grants from the National Natural Science Foundation of China(No.81772539,81972238);the Fundamental Research Funds for the Central Universities of China-Xiamen University(No.20720180048).

摘　　要：Severe immune responses regulate the various clinical hepatic injuries, includingautoimmune hepatitis and acute viral hepatitis. N6-methyladenosine (m6A) modification is acrucial regulator of immunity and inflammation. However, the precise role of YTHDF1 in Tcell-mediated hepatitis remains incompletely characterized. To address this, we utilizedConcanavalin A (ConA)-induced mouse liver damage as an experimental model for T cell-mediated hepatitis. Our findings found that hepatic YTHDF1 protein rapidly decreased during ConAinduced hepatitis, and YTHDF1-deficient (Ythdf1^(-/-)) mice showed more susceptibility toConA-induced liver injury, along with an intensified inflammatory storm accompanied by aggravated hepatic inflammatory response via ERK and NF-κB pathways. Interestingly, hepatic-specific over-expression or deletion of YTHDF1 exhibited redundancy in ConA-induced liver injury.Validation in bone marrow chimeric mice confirmed the necessity of YTHDF1 in hematopoieticcells for controlling the response to ConA-induced hepatitis. Additionally, our data revealedthat YTHDF1 deletion in macrophages exacerbated the inflammatory response induced by lipopolysaccharide. In summary, our study uncovered that YTHDF1 deficiency exacerbates the immune response in ConA-induced hepatitis by modulating the expression of inflammatorymediators, highlighting the potential of YTHDF1 as a therapeutic target for clinical hepatitis.

关 键 词：Concanavalin A HEPATITIS Inflammatory response N6-methyladenine YTHDF1 

分 类 号：R575.1[医药卫生—消化系统]