Molecular and bioinformatic mechanism of asiaticoside on macrophage-mediated keloid pathogenesis.

BACKGROUND

Keloid is a fibroproliferative skin disorder driven by dysregulated inflammation and fibrosis, involving complex interactions between keloid fibroblasts (KFs) and immune cells. Although macrophages are implicated in keloid pathogenesis, the exact mechanisms remain poorly defined. Asiaticoside, a natural triterpene molecule, has shown therapeutic potential for pathological scarring, yet its molecular mechanisms warrant further investigation.

PURPOSE: This study aims to elucidate the macrophage subtype-specific contributions to keloid progression and to investigate the anti-inflammatory and anti-fibrotic therapeutic efficacy of asiaticoside.

METHODS

In vitro co-culture models were established to assess the interactions between KFs and macrophages. Phenotypic changes, inflammation, fibrogenesis, and macrophage polarization were evaluated. Asiaticoside was tested at various doses for its effects on these pathological phenotypes. Macrophage or human monocyte pre‑treated with asiaticoside were co‑cultured with untreated KFs to determine the indirect inhibitory effect of asiaticoside on KF activation. Proteomic, phosphoproteomic, and molecular docking analyses were conducted to explore underlying mechanisms.

RESULTS

Both M1 and M2 macrophages exacerbated KFs proliferation, inflammation, and fibrogenesis, while KFs reciprocally promoted M2 macrophage polarization. Asiaticoside dose-dependently suppressed pathological phenotypes of KFs and macrophages and attenuated their pro-inflammatory and pro-fibrogenic cross-activation. Pre-treatment of macrophages or monocytes with asiaticoside inhibited their ability to activate KFs. Proteomic and phosphoproteomic profiling revealed that asiaticoside disrupted multiple keloid-associated pathogenic pathways. Molecular docking further identified high-affinity interactions between asiaticoside and pro-inflammatory factors.

CONCLUSION

Asiaticoside exerts a dual therapeutic mechanism by concurrently inhibiting macrophage-driven inflammation and fibroblast-driven fibrogenesis, positioning it as a promising multi-targeting agent for keloid and related fibrotic diseases.