The study investigates the role of N6-methyladenosine (m6A) methyltransferase METTL14 in the progression of metabolism-associated fatty liver disease (MAFLD). Key findings include: 1. **METTL14 Downregulation in MAFLD**: METTL14 expression is significantly downregulated in the livers of patients and murine models of MAFLD. Hepatocyte-specific depletion of METTL14 exacerbates lipid accumulation, liver injury, and fibrosis, while overexpression of METTL14 ameliorates these conditions in mice fed a high-fat diet (HFD). 2. **Mechanistic Studies**: In vivo and in vitro studies show that METTL14 downregulation decreases the level of GLS2 by affecting its translation efficiency mediated by YTHDF1 in an m6A-dependent manner. This leads to an oxidative stress microenvironment and recruits Cx3cr1+ Ccr2+ monocyte-derived macrophages (Mo-macs). 3. **Cx3cr1+ Ccr2+ Mo-macs and S100A4**: Cx3cr1+ Ccr2+ Mo-macs, which can be categorized into M1-like macrophages and S100A4-positive macrophages, activate hepatic stellate cells (HSCs) to promote liver fibrosis. CX3CR1 activation of the CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1+ Ccr2+ Mo-macs promotes S100A4 expression. 4. **Therapeutic Implications**: Restoration of METTL14 or GLS2, or interference with the CX3CR1/MyD88/NF-κB signaling pathway, ameliorates liver injuries and fibrosis in MAFLD models. These findings suggest potential therapeutic strategies for treating MAFLD progression.The study investigates the role of N6-methyladenosine (m6A) methyltransferase METTL14 in the progression of metabolism-associated fatty liver disease (MAFLD). Key findings include: 1. **METTL14 Downregulation in MAFLD**: METTL14 expression is significantly downregulated in the livers of patients and murine models of MAFLD. Hepatocyte-specific depletion of METTL14 exacerbates lipid accumulation, liver injury, and fibrosis, while overexpression of METTL14 ameliorates these conditions in mice fed a high-fat diet (HFD). 2. **Mechanistic Studies**: In vivo and in vitro studies show that METTL14 downregulation decreases the level of GLS2 by affecting its translation efficiency mediated by YTHDF1 in an m6A-dependent manner. This leads to an oxidative stress microenvironment and recruits Cx3cr1+ Ccr2+ monocyte-derived macrophages (Mo-macs). 3. **Cx3cr1+ Ccr2+ Mo-macs and S100A4**: Cx3cr1+ Ccr2+ Mo-macs, which can be categorized into M1-like macrophages and S100A4-positive macrophages, activate hepatic stellate cells (HSCs) to promote liver fibrosis. CX3CR1 activation of the CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1+ Ccr2+ Mo-macs promotes S100A4 expression. 4. **Therapeutic Implications**: Restoration of METTL14 or GLS2, or interference with the CX3CR1/MyD88/NF-κB signaling pathway, ameliorates liver injuries and fibrosis in MAFLD models. These findings suggest potential therapeutic strategies for treating MAFLD progression.