Reprogramming cysteine metabolism via METTL14-SLC7A11 axis promotes the progression of NAFLD and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) constitute significant global health challenges, with their prevalence exacerbated by shifts in lifestyle and dietary habits. Cysteine metabolism is intricately linked to the synthesis of reductive glutathione (GSH) and the maintenance of redox homeostasis, both of which are essential for cellular viability. N6-methyladenosine (m6A) methylation has emerged as a critical regulatory mechanism influencing metabolic pathways and redox balance in the context of NAFLD and HCC. This study aimed to elucidate the role of METTL14 in cysteine metabolism and the progression of NAFLD and HCC in vivo by examining the amino acid metabolic profile of NAFLD-affected livers using a hepatocyte-specific METTL14 knockout mouse model. Our results demonstrate that deletion of METTL14 reduces m6A methylation of SLC7A11 mRNA, thereby impairing cystine uptake, disrupting cysteine-dependent GSH synthesis, and compromising mitochondrial structure and function. These alterations culminate in the accumulation of reactive oxygen species, enhanced lipid peroxidation, increased cell death, and the accelerated progression of NAFLD and diethylnitrosamine-induced HCC. Collectively, these findings suggest that targeting the METTL14-SLC7A11-cysteine-GSH axis may offer a novel therapeutic approach for mitigating the advancement of NAFLD and HCC.