Inflammation and ferroptosis play important roles in metabolic?dysfunction-associated?steatotic?liver?disease (MASLD) pathogenesis. It is necessary to identify inflammation-associated ferroptosis regulators (IAFRs) in MASLD progression and potential drugs for MASLD treatment. The MASLD-related dataset GSE49541 was analyzed to identify differentially expressed genes. Identification of crucial genes in MASLD pathogenesis was archived with WGCNA algorithm. Genes related to inflammation and ferroptosis were obtained from GSEA database and FerrDb database. After IAFRs were obtained from the intersection, virtual screening of natural drugs targeting early growth response protein 1 (EGR1) was performed. MASLD models were constructed, and treated with (-)Epicatechin (EPI) or not. Then the severity of MASLD in mice was evaluated by histological analysis, blood biochemical examination, etc., and the injury of in vitro hepatocytes was detected by cell viability assay, flow cytometry, etc. ELISA was applied to evaluate the inflammatory response, and reactive oxide species, iron load, and ferroptosis markers were detected. Western blot was used to detect the regulatory effects of EPI on NF-κB and Nrf2 pathways. Six IAFRs in MASLD pathogenesis were identified, including EGR1, GSTZ1, SLC38A1, FH, HELLS and MT1G. EPI had good binding affinity with EGR1, which reversed HFD-induced weight and liver weight gain in mice, and inhibit inflammatory response and ferroptosis, and effectively ameliorated liver injury. EPI also reduced free fatty acids-induced injury of hepatocytes. Additionally, EPI regulates lipid metabolism, inflammation, oxidative stress, and ferroptosis in MASLD mainly through NF-κB and Nrf2 pathways. Collectively, EPI targets EGR1 to ameliorate liver injury in MASLD.