METTL14 Downregulation Accelerates HBV-Related Cirrhosis and Hepatocellular Carcinoma by Promoting Type I Interferon Release via the cGAS-STING Pathway Through m6A Modification.
The pathogenesis of Hepatitis B virus (HBV)-related cirrhosis and hepatocellular carcinoma (HCC) has not been fully elucidated at present. While METTL14 is crucial in innate immunity, its specific role in HBV-related liver disease progression is unclear. We analyzed METTL14 expression in patient tissues and bioinformatics datasets. Mouse models of HBV-related cirrhosis and HCC were established to evaluate liver injury, fibrosis, and tumorigenesis. Mechanistic studies utilized MeRIPqPCR, RIP, and Actinomycin D assays, and hepatocyte-stellate cell co-cultures to investigate METTL14's impact on cGAS mRNA stability, the cGAS-STING pathway, and IFNB1 secretion. METTL14 was downregulated in HBV infection, cirrhosis, and HCC. METTL14 knockdown aggravated liver injury, fibrosis, and tumor formation in mice. Mechanistic studies revealed that METTL14 overexpression in HBV-infected hepatocytes promoted the degradation of cGAS mRNA by increasing its m6A modification, thereby suppressing the cGAS-STING pathway activation and IFNB1 release. Consequently, METTL14 overexpression inhibited stellate cell activation, which was reversed by cGAS-STING agonists. Downregulation of METTL14 reduces the degradation of cGAS mRNA through m6A modification, facilitates the cGAS-STING pathway activation and IFNB1 release, thereby accelerating HBV-related cirrhosis and HCC progressions.