METTL14 downregulation drives S100A4^(+)monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression  

作　　者：Yue-fan Wang Wen-li Zhang Zhi-xuan Li Yue Liu Jian Tan Hao-zan Yin Zhi-chao Zhang Xian-jie Piao Min-hao Ruan Zhi-hui Dai Si-jie Wang Chen-yang Mu Ji-hang Yuan Shu-han Sun Hui Liu Fu Yang 

机构地区：[1]The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University,200438 Shanghai,China [2]The Department of Medical Genetics,Naval Medical University,200433 Shanghai,China [3]Translational Medicine Research Center,Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital,100048 Beijing,China [4]The Department of Pharmaceutical Analysis,School of Pharmacy,Naval Medical University,200433 Shanghai,China [5]Key Laboratory of Biosafety Defense,Ministry of Education,200433 Shanghai,China [6]Shanghai Key Laboratory of Medical Biodefense,200433 Shanghai,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第5期2176-2192,共17页信号转导与靶向治疗（英文）

基　　金：This research was supported by grants from the National Key Research and Development Program of China(2023YFC2505900,2016YFC1302303);the National Natural Science Foundation of China(nos.81972657 and 81830085).

摘　　要：Without intervention,a considerable proportion of patients with metabolism‐associated fatty liver disease(MAFLD)will progress from simple steatosis to metabolism‐associated steatohepatitis(MASH),liver fibrosis,and even hepatocellular carcinoma.However,the molecular mechanisms that control progressive MAFLD have yet to be fully determined.Here,we unraveled that the expression of the N6-methyladenosine(m6A)methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD,whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation,liver injury,and fibrosis.Conversely,hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet(HFD).Notably,in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner,which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1^(+)Ccr2^(+)monocyte-derived macrophages(Mo-macs).In detail,Cx3cr1^(+)Ccr2^(+)Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells(HSCs)to promote liver fibrosis.Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1^(+)Ccr2^(+)Mo-macs.Restoration of METTL14 or GLS2,or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and fibrosis.Taken together,these findings indicate potential therapies for the treatment of MAFLD progression.

关 键 词：S100A4 MYD88 METABOLISM 

分 类 号：R575.5[医药卫生—消化系统]