The etiology of alcoholic fatty liver (AFL) is complex, representing the early reversible stage of alcohol-associated liver disease (ALD). Alleviating oxidative stress, reducing inflammation, and preventing the development of liver fibrosis are considered the most effective strategies for treating AFL. Consequently, we selected isoliquiritigenin (ISL), a flavonoid compound recognized for its anti-inflammatory, antioxidant, and anticancer pharmacological properties. In this study, we investigated the role and mechanism of ISL in AFL. Mechanistic studies revealed that ISL reduces the expression of pro-inflammatory factors by inhibiting annexin A2 (ANXA2), which is involved in the inflammatory response, along with the downstream signaling pathways, activator of signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa-B (NF-κB). Additionally, ISL activates the nuclear factor erythroid 2 like 2 (Nrf2) antioxidant pathway and enhances antioxidant enzyme activity, thereby reducing liver inflammation and oxidative damage while promoting hepatocyte repair. We identified the significantly differentially expressed protein transgelin 2 (TAGLN2) using tandem mass tag (TMT) proteomics technology. Notably, ISL inhibits the expression of TAGLN2 both in vivo and in vitro, alleviating AFL by blocking the ANXA2/STAT3 signaling pathway. Furthermore, we demonstrated that TAGLN2 serves as a direct target for ISL in the treatment of AFL and regulates STAT3 through its interaction with ANXA2. In summary, this study provides a theoretical basis for considering ISL as a novel drug monomer for treating AFL and offers a promising therapeutic strategy for AFL.
