Effect of metformin on nonalcoholic fatty liver based on meta-analysis and network pharmacology

Background: Whether metformin is related to nonalcoholic fatty liver disease (NAFLD) is controversial. Our aim was to investigate the relationship between metformin and NAFLD that may predict the metformin potential of these lesions and new prevention strategies in NAFLD patients. Methods: The meta-analysis was analyzed by Revman 5.3 softwares systematically searched for works published through July 29, 2022. Network pharmacology research based on databases, Cytoscape 3.7.1 software and R software respectively. Results: The following variables were associated with metformin in NAFLD patients: decreased of alanine aminotransferase (ALT) level (mean difference [MD] = -10.84, 95% confidence interval [CI] = -21.85 to 0.16, P = .05); decreased of aspartate amino transferase (AST) level (MD = -4.82, 95% CI = -9.33 to -0.30, P = .04); decreased of triglyceride (TG) level (MD = -0.17, 95% CI = -0.26 to -0.08, P = .0002); decreased of total cholesterol (TC) level (MD = -0.29, 95% CI = -0.47 to -0.10, P = .003); decreased of insulin resistance (IR) level (MD = -0.42, 95% CI = -0.82 to -0.02, P = .04). In addition, body mass index (BMI) (MD = -0.65, 95% CI = -1.46 to 0.16, P = .12) had no association with metformin in NAFLD patients. 181 metformin targets and 868 NAFLD disease targets were interaction analyzed, 15 core targets of metformin for the treatment of NAFLD were obtained. The effect of metformin on NAFLD mainly related to cytoplasm and protein binding, NAFLD, hepatitis B, pathway in cancer, toll like receptor signaling pathway and type 2 diabetes mellitus (T2DM). The proteins of hypoxia inducible factor-1 (HIF1A), nuclear factor erythroid 2-related factor (NFE2L2), nitric oxide synthase 3 (NOS3), nuclear receptor subfamily 3 group C member 1 (NR3C1), PI3K catalytic subunit alpha (PIK3CA), and silencing information regulator 2 related enzyme 1 (SIRT1) may the core targets of metformin for the treatment of NAFLD. Conclusion: Metformin might be a candidate drug for the treatment of NAFLD which exhibits therapeutic effect on NAFLD patients associated with ALT, AST, TG, TC and IR while was not correlated with BMI. HIF1A, NFE2L2, NOS3, NR3C1, PIK3CA, and SIRT1 might be core targets of metformin for the treatment of NAFLD.