Harmine Derivative H-2-104 Alleviates Echinococcus granulosus-Induced Pulmonary Fibrosis in Mice by Inhibiting Fibroblast Activation and Inducing DNA Damage.

BACKGROUND

Pulmonary fibrosis (PF) secondary to Echinococcus granulosus infection is a severe complication with limited therapeutic options. Harmine (HM) exhibits antifibrotic potential but is restricted by significant neurotoxicity. This study aimed to evaluate the therapeutic efficacy and underlying mechanism of HM derivative H-2-104 in a clinically relevant E. granulosus-induced PF mouse model, and to clarify its advantages over parent compound HM.

METHODS

A mouse model of E. granulosus-induced PF was established, and treated with H-2-104 (25 or 50 mg/kg) or nintedanib for 21 days. Lung function, histopathology, hydroxyproline (HYP), inflammatory cytokines, and fibrosis-related protein expression were assessed. In vitro, human embryonic lung fibroblasts (MRC-5) were activated with TGF-β1 and treated with H-2-104. Cell viability, migration, apoptosis, differentiation, DNA damage, and related gene expression were evaluated.

RESULTS

H-2-104 significantly improved lung function, alleviated pathological damage, and collagen deposition, decreased HYP, TGF-β1, TNF-α, IL-6, and IL-1β, elevated IL-10, and downregulated α-smooth muscle actin (α-SMA), collagen I, and fibronectin. Importantly, H-2-104 showed no obvious neurotoxicity and exhibited better safety than HM. In vitro, H-2-104 inhibited TGF-β1-induced MRC-5 cell viability (IC50 = 13.49 µg/mL), migration, and fibroblast-to-myofibroblast differentiation, while promoting apoptosis along with increased DNA damage in a dose-dependent manner. Additionally, H-2-104 downregulated the expression of fibrosis-related genes and upregulated DNA damage-related genes (H2AX, ATR, and RAD51) in TGF-β1-induced MRC-5 cells.

CONCLUSION

This study establishes H-2-104 as a promising antifibrotic candidate for E. granulosus-induced PF, using a clinically meaningful parasitic infection-associated fibrosis model. H-2-104 retains strong antifibrotic efficacy while overcoming the neurotoxicity limitation of HM. Mechanistically, the activation of DNA damage response is correlated with the antifibrotic activities of H-2-104, providing a new perspective for targeting fibroblast activation in PF therapy.