线粒体功能障碍是非酒精性脂肪肝（NAFLD）的重要致病因素。甲基转移酶样 14 (METTL14) 与线粒体裂变过程有关。本研究旨在探讨METTL14在NAFLD线粒体功能中的作用机制。我们首先建立了NAFLD小鼠模型和细胞模型，记录体重和肝脏重量并检查肝组织的病理变化。随后，检测肝功能指标（天冬氨酸转氨酶[AST]、丙氨酸转氨酶[ALT]、总胆固醇[TC]和甘油三酯[TG]）、炎症标志物（肿瘤坏死因子-α[TNF-α]、白细胞介素[ IL]-6 和 IL-1β）和线粒体功能障碍指标（裂变 1 蛋白 [Fis1]、动力相关蛋白 1 [Drp1]、线粒体融合蛋白 2 [Mfn2]、SID1 跨膜家族成员 2 [SIDT2] 和线粒体膜评估了肝脏和细胞中的潜在[MMP])。对初级 microRNA (pri-miRNA) 的 N6-甲基腺苷 (m6A) 修饰水平和 pri-miR-34a 上的 m6A 富集进行了定量。利用免疫共沉淀和双荧光素酶报告基因测定来验证基因相互作用。我们的研究结果显示，NAFLD 小鼠和细胞模型中 METTL14 表达高度升高。沉默 METTL14 可减少 NAFLD 小鼠的体重增加并减轻不良肝功能指数、炎症、肝脂肪变性和结构损伤。它还导致肝脏和细胞中 Fis1/Drp1 水平降低以及 MMP/Mfn2 水平增加。此外，METTL14增加了m6A水平，促进DiGeorge综合征关键区8（DGCR8）与pri-miR-34a的结合，从而增强了miR-34a-5p的表达。数据库和双荧光素酶报告基因检测表明 miR-34a-5p 可以抑制 SIDT2 表达。 miR-34a-5p 的过度表达或 SIDT2 表达的抑制抵消了 METTL14 沉默对线粒体稳态失衡的缓解作用。总之，METTL14 通过 m6A 修饰调节 miR-34a-5p/SIDT2 轴，损害 NAFLD 中的线粒体稳态。

Mitochondrial dysfunction is an important pathogenic factor in non-alcoholic fatty liver disease (NAFLD). Methyltransferase-like 14 (METTL14) has been implicated in mitochondrial fission processes. This research aimed to investigate the mechanism of METTL14 in the mitochondrial function of NAFLD. We first established NAFLD mouse models and cell models, recording body and liver weights and examining pathological changes in liver tissues. Subsequently, serum levels of liver function indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total cholesterol [TC], and triglycerides [TG]), inflammatory markers (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, and IL-1β), and mitochondrial dysfunction indicators (fission 1 protein [Fis1], dynamin-related protein 1 [Drp1], mitofusin 2 [Mfn2], SID1 transmembrane family member 2 [SIDT2], and mitochondrial membrane potential [MMP]) in the liver and cells were evaluated. The N6-methyladenosine (m6A) modification level of primary microRNA (pri-miRNA) and m6A enrichment on pri-miR-34a were quantified. Co-immunoprecipitation and dual-luciferase reporter gene assays were utilized to validate gene interactions. Our findings revealed highly elevated METTL14 expression in NAFLD mouse and cell models. Silencing METTL14 reduced weight gain and mitigated adverse liver function indices, inflammation, hepatic steatosis, and structural damage in NAFLD mice. It also led to a decrease in Fis1/Drp1 levels and an increase in MMP/Mfn2 in the liver and cells. Moreover, METTL14 increased the m6A level, promoting the binding of DiGeorge syndrome critical region 8 (DGCR8) to pri-miR-34a, which enhanced miR-34a-5p expression. Databases and dual-luciferase reporter gene assays indicated that miR-34a-5p could suppress SIDT2 expression. The overexpression of miR-34a-5p or inhibition of SIDT2 expression negated the alleviative effects of METTL14 silencing on mitochondrial homeostasis imbalance. In conclusion, METTL14, through m6A modification, modulates the miR-34a-5p/SIDT2 axis, impairing mitochondrial homeostasis in NAFLD.