Oleanolic acid alleviates hepatic fibrosis by inhibiting liver macrophage recruitment and polarization

Background: Liver fibrosis is a key pathological step in chronic liver disease progression, yet effective therapies are scarce. Oleanolic acid (OA) exhibits hepatoprotective effects, but whether it ameliorates fibrosis by regulating macrophages is unknown. This study hypothesized that OA attenuates liver fibrosis by suppressing macrophage recruitment and polarization.

Methods: A CCl₄-induced mouse fibrosis model was established with or without macrophage depletion. Hepatic pathology, liver function, and fibrosis markers were assessed. Macrophage markers and M1/M2 subsets were analyzed. Macrophage-stellate cell crosstalk was studied via conditioned medium co-culture. Transcriptome Sequencing and r-FosB rescue experiments identified the underlying mechanism.

Results: OA dose-dependently alleviated CCl₄-induced liver fibrosis in mice, reducing serum markers of liver injury, fibrosis, and inflammation, as well as downregulating TGF-β and FN1 expression. OA significantly suppressed macrophage recruitment and decreased M1/M2 proportions and marker expression, with no significant cytotoxicity to macrophages at the tested concentrations. Macrophage depletion markedly attenuated OA's anti-fibrotic effects. In vitro, OA directly inhibited M1/M2 polarization and indirectly suppressed LX-2 cell activation via paracrine regulation. Transcriptomics identified FosB as a key downregulated gene; recombinant r-FosB reversed OA's inhibitory effects on macrophage polarization and stellate cell activation.

Conclusion: OA alleviates liver fibrosis by inhibiting FosB/ΔFosB-mediated macrophage recruitment and polarization imbalance, thereby regulating macrophage-stellate cell interactions. This study provides novel evidence for its clinical application.