Yohimbine attenuates bleomycin-induced skin fibrosis by modulating the PI3K/Akt-MAPK signaling: an integrated network pharmacology and in vivo study.

Skin fibrosis is a chronic inflammatory disorder characterized by excessive extracellular matrix (ECM) deposition and aberrant fibroblast activation, leading to tissue stiffening and progressive functional impairment. Despite its clinical prevalence, no FDA-approved therapies are currently available, highlighting a significant unmet medical need. The present study investigated the anti-fibrotic potential of yohimbine using an integrated network pharmacology approach and a bleomycin (BLM)-induced murine skin fibrosis model. Network pharmacology identified 168 overlapping targets between yohimbine and skin fibrosis, while KEGG enrichment highlighted the PI3K/Akt and MAPK pathways as key antifibrotic signaling mechanisms. Subcutaneous administration of BLM (3 mg/kg) for 28 days induced marked skin fibrosis compared with sham control. Yohimbine treatment at 2.5 and 5 mg/kg attenuated bleomycin (BLM)-induced skin fibrosis, with the 5 mg/kg dose demonstrating a more consistent antifibrotic response compared with the BLM group. Molecular analyses demonstrated that yohimbine suppressed the pro-fibrotic (Ccn2, α-Sma, Vimentin, Zeb, and Snail) and inflammatory markers (Tnf-α) expression. Furthermore, yohimbine restored the expression of antifibrotic (Hgf) and antioxidant (Gstp1, Nrf2, and Hmox1) markers, while reducing ECM-associated markers, including Fibronectin (FN1) and Collagen Type III (COL3α1), at both mRNA and protein levels. Histopathological, Masson's trichrome, and Sirius red/fast green collagen staining analysis further demonstrated that yohimbine treatment significantly (p < 0.05) reduced collagen deposition and restored normal skin architecture. Collectively, these findings demonstrate that yohimbine attenuates skin fibrosis by suppressing inflammatory and fibrotic responses, potentially through modulation of PI3K/Akt-MAPK signaling, and may represent a potential lead for further investigation in fibrotic skin disorders.