BackgroundThe worldwide burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising sharply, powered by high prevalence of obesity and its associated metabolic insults. Though urgent, definitive treatment is not yet available. Empagliflozin, a sodium glucose co-transporter inhibitor has been suggested in both human and animal studies to have diverse beneficial effects in MASLD by anti-inflammation and anti-oxidative stress effects, but many of the underlying mechanisms remain unexplained. The main aim of this systematic review and meta-analysis was to evaluate the effects of empagliflozin’s in preclinical animal studies trying to view new horizons for future treatment of MASLD.Methodswe searched the related animal preclinical studies in databases including Scopus, Web of Science, Cochrane library, Wily online library and PubMed. The research team screened the literature and extracted data; any discrepancies were resolved by the research team leader through discussion. The quality of research methods was assessed by SYRCLE (systematic review center for laboratory animal experimentation) risk of bias tool. The meta-analysis was guided by the Cochrane Handbook; statistical analyses were conducted via RevMan 5.4 offline version and Comprehensive Met analysis V3 software.ResultsOur meta-analysis included 17 studies, involving 584 animals. In comparison with the model group, empagliflozin significantly reduced steatosis markers including hepatic burden of lipids, including triglycerides and cholesterol, NAFLD Activity Score (NAS) and total serum cholesterol (TC). It also significantly reduced hepatic fibrosis markers including fibrosis grade, transforming growth factor-β (TGF-β) and collagen type I alpha 1 chain) COL1A1). Beyond its anti-steatofibrotic effects, empagliflozin significantly downregulated hepatic expression of inflammatory and oxidative markers including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and malondialdehyde (MDA). Moreover, empagliflozin significantly improved glycemic indices including Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum insulin, and fasting blood sugar (FBS).ConclusionEmpagliflozin significantly protected the liver against steatosis and fibrosis by mitigating hepatic inflammation, oxidative stress and insulin resistance.