Liquiritigenin ameliorates adipocyte insulin resistance by inhibiting pro-inflammatory polarization of macrophages via regulation of the mtROS/OXPHOS axis.

Obesity-induced insulin resistance (IR) is closely associated with chronic inflammation and metabolic dysfunction in adipose tissue, in which macrophage polarization plays a pivotal role. Liquiritigenin (LQ), a natural flavonoid derived from licorice, exhibits potential metabolic regulatory effects; however, its role in high-fat diet (HFD)-induced obesity and insulin resistance, as well as the underlying mechanisms, remains unclear. In this study, an HFD-induced obese mouse model combined with multi-omics analyses and an in vitro co-culture system was employed to investigate the effects of LQ. LQ significantly improved glucose tolerance, insulin sensitivity, and lipid metabolism, and restored the expression of p-IRS1/IRS1, p-AKT/AKT, and GLUT4 in epididymal adipose tissue. Integrated analyses of network pharmacology, transcriptomics, and metabolomics revealed that LQ markedly reversed HFD-induced alterations in oxidative stress, mitochondrial dysfunction, and inflammatory pathways. Mechanistically, palmitic acid (PA) at physiologically relevant concentrations did not directly induce insulin resistance in adipocytes but instead promoted macrophage polarization toward the pro-inflammatory M1 phenotype, thereby impairing adipocyte insulin signaling. Further investigation showed that PA and HFD increased mitochondrial reactive oxygen species (mtROS), disrupted oxidative phosphorylation (OXPHOS), and induced mitochondrial dysfunction in macrophages, ultimately driving M1 polarization; these effects were markedly attenuated by the mtROS scavenger Mito-TEMPO. In contrast, LQ reduced mtROS levels, restored OXPHOS function, and maintained mitochondrial homeostasis, thereby suppressing pro-inflammatory macrophage polarization and improving insulin signaling and glucose uptake in adipocytes. Notably, these effects were more pronounced than those observed with dexamethasone under the same experimental conditions. These protective effects were abolished by the mtROS activator DMNQ. In conclusion, LQ alleviates adipose tissue insulin resistance by modulating macrophage polarization through the mtROS/OXPHOS axis, providing new mechanistic insights into immunometabolic regulation and supporting of applying LQ as a potential phytotherapy strategy for obesity-related metabolic disorders.