BMI1 Overexpression Alleviates Metabolic Syndrome-Related Liver Injury by Inhibiting the Activation of the METTL3/AHNAK Axis

Abnormal protein levels have been demonstrated to contribute to the progression of various diseases, including metabolic syndrome (MetS). Here, we speculated that the downregulation of BMI1 might lead to the failure of METTL3 degradation and contribute to METTL3 overexpression in MetS-related liver injury. Rats were fed a diet consisting of a high proportion of fat and fructose (HFHF), and genetic intervention was performed via tail vein injection of liver-specific AAV vectors. In the liver tissue of rats induced by HFHF, BMI1 was downregulated, while METTL3 and AHNAK were upregulated. BMI1 overexpression suppressed HOMA-IR levels, downregulated the serum levels of TC, TG, ALT, and AST, and reduced oxidative stress-related markers and the number of lipid droplets in liver tissues in rats with HFHF. BMI1 overexpression promoted the ubiquitination and degradation of METTL3 in BRL 3A cells, while METTL3 overexpression enhanced the m6A modification of AHNAK, leading to upregulation of AHNAK. Overexpression of METTL3 or AHNAK attenuated the mitigating effect of BMI1 overexpression in vivo and in vitro by activating the TGF-β/SMAD signaling. These findings suggest that BMI1 overexpression alleviates MetS-associated liver injury by inhibiting AHNAK m6A methylation through promoting METTL3 degradation, thereby suppressing the TGF-β/SMAD signaling.