A quercetin derivative from Sarcostemma brevistigma mitigates silica-induced pulmonary injury via regulation of TLR4/NF-κB and Nrf2 signaling pathways.

Silicosis is a progressive occupational lung disease characterized by persistent inflammation, oxidative stress, and fibrotic remodelling, largely mediated by activation of the TLR4/NF-κB pathway and suppression of endogenous antioxidant defences. The molecular significance of Sarcostemma brevistigma's quercetin derivatives in silica-induced lung injury is still unclear, despite the plant's abundance of bioactive flavonoids with documented anti-inflammatory and antioxidant qualities. This study used a mouse model of SiO2-induced lung injury to examine the anti-inflammatory, antioxidant, and antifibrotic properties of a prenylated quercetin derivative (SA) that was isolated from S. brevistigma.

Methods

Five groups of male mice were used: vehicle control, SiO2 alone (100 mg/kg/day), SiO2 + SA (50 mg/kg every second day for 6 weeks), SiO2 + SA (100 mg/kg every second day for 6 weeks), and SA alone (100 mg/kg every second day for 42 days). ELISA was used to measure the amounts of TNF-α, IL-1β, IL-6, and C-reactive protein in the serum. Biochemical methods were used to evaluate oxidative stress parameters. Histopathological evaluation of lung tissues was performed using Western blot analysis of TLR4, MyD88, NF-κB/p-NF-κB, Nrf2, HO-1, and NQO1, as well as H&E and Masson's trichrome staining and TNF-α immunohistochemistry. SiO2 exposure markedly elevated systemic and pulmonary pro-inflammatory cytokines, increased malondialdehyde and hydrogen peroxide levels, depleted antioxidant enzymes, activated TLR4/MyD88/NF-κB signaling, and suppressed Nrf2/HO-1/NQO1 expression, accompanied by pronounced inflammatory infiltration and fibrosis. SA treatment dose-dependently reduced cytokine and oxidative stress markers, restored GSH, SOD, CAT, and GPx activities, downregulated TLR4, MyD88, and p-NF-κB, and reactivated Nrf2-dependent cytoprotective pathways. Histological and immunohistochemical analyses confirmed preservation of alveolar architecture, reduced collagen deposition, and diminished TNF-α expression. SA exerts robust anti-inflammatory, antioxidant, and antifibrotic effects against SiO2-induced lung injury by concurrently suppressing TLR4/NF-κB signaling and activating Nrf2-regulated defense mechanisms, highlighting its potential as a natural therapeutic candidate for silicosis.