Pirfenidone–Silymarin Combination Mitigates Paraquat-Induced Lung Fibrosis Via Oxidative and Pro-Fibrotic Pathway Modulation Publisher



Rasooli R ; Mandegary A ; Aghebatbekheir S
Source: Natural Product Communications Published:2026

Abstract

Background & Objective: Paraquat (PQ), a widely used heterocyclic herbicide, has caused many deaths due to acute lung fibrosis, which demands more effective therapies. Since multiple co-activated pathways are involved in the pathogenesis of fibrosis, targeting these pathways seems to be a reasonable strategy for a successful treatment. The present study aimed to evaluate the therapeutic effect of a combination of pirfenidone and silymarin in paraquat-induced lung fibrosis in rats. Methods: Forty Wistar rats were randomly divided into five groups (control, PQ, SM, PQ + SM, and negative control group). Pulmonary fibrosis was induced by a single dose of 20 mg/kg PQ in rats and followed by oral treatment regimens. The comparison of effects was performed by evaluating histopathological changes, hydroxyproline content, tissue oxidative stress parameters, and the expression of pro-inflammatory and pro-fibrotic genes, including TGF-β1, TNF-α, TIMP-1, and MMP-2, using real-time RT-PCR. Results: Pathological changes, including increased lung hydroxyproline levels, were observed in the lung tissues of the paraquat-treated group. Paraquat also caused oxidative stress and an increase in profibrotic gene expression. Pirfenidone and silymarin were able to solely recover the pathological changes caused by paraquat, decrease lipid peroxidation, and restore the antioxidant enzymes to near-normal values. The combination of pirfenidone and silymarin significantly reduced the hydroxyproline content. At the molecular level, the expressions of TGF-β1, TNF-α, TIMP-1, and MMP-2 genes were decreased in the treated rats. Concurrent therapy by pirfenidone plus silymarin showed more potent anti-fibrotic and anti-inflammatory effects. Conclusion: In conclusion, pirfenidone plus silymarin holds promise as a combination therapy for treating PQ-induced pulmonary fibrosis. © The Author(s) 2026. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).