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

Abstract

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.

Unraveling the role of METTL14 in metabolic dysfunction-associated fatty liver disease: insights and therapeutic implications

“…The recent article published in Signal Transduction and Targeted Therapy sheds light on the significance of N6-methyladenosine (m6A) methyltransferase-like protein METTL14 in mitigating the progression of metabolic dysfunction-associated fatty liver disease (MAFLD). 1 In this study, Wang et al elucidated the downregulation of METTL14 in hepatocytes from both MAFLD patients and high-fat diet (HFD)-induced MAFLD mouse models, underscoring its pivotal role in maintaining hepatic lipid and redox homeostasis in normal livers. Dysregulation of METTL14 emerges as a contributing factor to MAFLD development.…”