Baoganning decoction mitigates liver fibrosis via regulating IDO1-mediated macrophage efferocytosis.

BACKGROUND

Liver fibrosis poses a significant global health challenge with limited treatments. Baoganning (BGN) decoction, a traditional Chinese medicine formula administered for liver fibrosis, has shown promise in preliminary studies by targeting indoleamine 2,3-dioxygenase 1 (IDO1), a key immunoregulator in the liver microenvironment. However, the precise underlying mechanisms remain unclear.

PURPOSE: This study aimed to elucidate the mechanism by which BGN alleviates liver fibrosis via IDO1-mediated regulation of macrophage function.

METHODS

The anti-fibrotic effects of BGN were evaluated using wild-type (WT) and IDO1-knockout (IDO1-/-) mice models of carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induce liver fibrosis. In vitro, a co-culture system of bone marrow-derived macrophages (BMDMs) and JS-1 cells was treated with BGN-containing serum. Computational simulations investigated the binding between IDO1 and the BGN-derived active component.

RESULTS

BGN significantly attenuated liver fibrosis in both WT models, reducing collagen deposition and fibrotic markers expression by approximately 50%. This effect was abolished in IDO1-/- mice, confirming IDO1 as a critical target. Mechanistically, BGN suppressed monocyte-derived macrophages recruitment and IDO1-mediated efferocytosis, thereby reducing TGF-β1 production and HSCs activation. 19α-Hydroxyasiatic acid (19α-HA) was identified as a key component of BGN that directly binds to IDO1 and potently inhibits efferocytosis and pro-fibrotic signaling.

CONCLUSION

This study provides novel evidence that BGN alleviates liver fibrosis by identifying its active component 19α-HA, and elucidating the underlying mechanism involving inhibition of IDO1-mediated macrophage efferocytosis. These findings elucidate the molecular foundation of BGN's multi-target effect and highlight the translational potential of 19α-HA for anti-fibrotic therapy.