Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, characterized by excess lipid deposition. Insulin resistance (IR) serves as a fundamental pathogenic factor in MAFLD. However, currently, there are no approved specific agents for its treatment. Farrerol, a novel compound with antioxidant and anti‐inflammatory effects, has garnered significant attention in recent years due to its hepatoprotective properties. Despite this, the precise underlying mechanisms of action remain unclear. In this study, a network pharmacology approach predicted protein tyrosine phosphatase non‐receptor type 1 (PTPN1) as a potential target for farrerol's action in the liver. Subsequently, the administration of farrerol improved insulin sensitivity and glucose tolerance in MAFLD mice. Furthermore, farrerol alleviated lipid accumulation by binding to PTPN1 and reducing the dephosphorylation of the insulin receptor (INSR) in HepG2 cells and MAFLD mice. Thus, the phosphoinositide 3‐kinase/serine/threonine‐protein kinases (PI3K/AKT) signalling pathway was active, leading to downstream protein reduction. Overall, the study demonstrates that farrerol alleviates insulin resistance and hepatic steatosis of MAFLD by targeting PTPN1.

Saturated fatty acid (SFA) accumulation in liver decreases hepatocyte lipophagy, a type of selective autophagy that degrades intracellular lipid droplets, leading to hepatic insulin resistance (IR), which contributes to simultaneous increases in liver glucose production and fat synthesis, resulting in hyperglycemia and dyslipidemia traits of type 2 diabetes mellitus (T2DM). Stromal cell derived factor‐1 (SDF‐1), a cytokine produced by hepatocytes, inhibits autophagy. In this study, we evaluated the hypothesis that SDF‐1 promoted hepatic IR via inhibiting hepatocyte lipophagy during T2DM. Furthermore, we probed the downstream pathway participating in the role of SDF‐1. The results showed that the neutralising of SDF‐1 improved hepatic IR via promoting hepatocyte lipophagy in a mouse high‐fat and high sucrose diet (HFHSD)‐induced T2DM model. In vitro, SDF‐1 expression and release increased in palmitic acid (PA, a kind of SFA)‐treated hepatocytes. Meanwhile, SDF‐1 bound to up‐regulated C‐X‐C chemokine receptor type 4 (CXCR4) and C‐X‐C chemokine receptor type 7 (CXCR7) on PA‐treated hepatocytes. Subsequently, SDF‐1 inhibited lipophagy in PA‐treated hepatocytes via CXCR4, rather than CXCR7. Finally, SDF‐1/CXCR4/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway‐inhibited lipophagy promotes PA‐induced hepatocyte IR. Collectively, this study discovered that SDF‐1 might inhibit lipophagy in SFA‐treated hepatocytes to promote hepatic IR via CXCR4/AKT/mTOR pathway.