Ameliorative Role of Silymarin in Methotrexate‐Induced Pulmonary Damage: A Multi‐Pathway Molecular Approach

Apr 6, 2026Journal of biochemical and molecular toxicology

Silymarin's protective role against lung damage caused by methotrexate through multiple molecular pathways

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Abstract

Silymarin significantly improved antioxidant status and reduced inflammation in rats treated with methotrexate.

Methotrexate treatment increased , indicated by elevated malondialdehyde and decreased antioxidant enzyme activities.
Increased levels of markers (Bax and Caspase-3) and decreased anti-apoptotic marker (Bcl-2) were observed with methotrexate treatment.
Methotrexate also heightened inflammatory markers, including NF-κB and TNF-α, suggesting an inflammatory response.
An increase in markers of (LC3A, LC3B, Beclin-1) was associated with methotrexate treatment.
Silymarin supplementation countered these effects, enhancing antioxidant defenses and modulating apoptotic and inflammatory responses.

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Methotrexate (MTX) is a medication that is frequently prescribed for the treatment of both malignant disorders and inflammatory pathologies. However, its use is limited by dose-dependent pulmonary toxicity. The present study investigated the protective effects of silymarin (SLM) against MTX-induced lung injury by evaluating , , , inflammation and histopathological changes in rats. Twenty-eight Wistar albino rats were assigned to the Control, SLM (50 mg/kg, p. o.), MTX (20 mg/kg, i. p.), and MTX + SLM groups. MTX treatment led to a significant elevation in malondialdehyde levels along with marked reductions in glutathione content and antioxidant enzyme activities, concomitant with decreased Nrf2 and HO-1 expression, indicating pronounced oxidative stress (p < 0.05). Additionally, MTX has been shown to raise Bax and Caspase-3 and diminish Bcl-2 while simultaneously inducing NF-κB, TNF-α, TLR-4, and HMGB1. This confirms the presence of increased inflammation and mitochondrial-dependent apoptosis (p < 0.05). Furthermore, MTX elevated the expression of LC3A, LC3B, and Beclin-1, suggesting an increase in autophagy (p < 0.05). SLM supplementation greatly improved antioxidant status, increased Nrf2/HO-1, decreased inflammatory signaling, modulated Caspase-3/Bax/Bcl-2 expression, and suppressed MTX-induced autophagy (p < 0.05). These biochemical findings were subsequently corroborated by histopathological analysis. In summary, the present study demonstrates that SLM offers a promising protective effect against MTX-induced pulmonary damage, operating through mechanisms involving antioxidant, anti-autophagic, anti-inflammatory and anti-apoptotic actions. These results underscore the potential of SLM as a complementary therapeutic agent in mitigating lung toxicity induced by chemotherapy agents.

Key numbers

59.67 nmol/g tissue

Increase in MDA Levels

MDA levels in MTX group compared to control

2.78 nmol/g tissue

Decrease in GSH Levels

GSH levels in MTX group compared to control

Histopathological Score

Score indicating lung injury severity in MTX group

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Ameliorative Role of Silymarin in Methotrexate‐Induced Pulmonary Damage: A Multi‐Pathway Molecular Approach

Abstract

Key numbers

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