Brusatol modulates autophagy to ameliorate pulmonary fibrosis by targeting Nrf2 in silicosis

Silicosis is a progressive lung fibrosis caused by silica exposure, with impaired autophagic degradation of alveolar macrophages recognized as a key pathogenic mechanism. Brusatol (Bru), an active compound from traditional Chinese medicine, has been suggested to regulate autophagy, but its therapeutic role in silicosis remains unclear.

A mouse silicosis model and silica-treated MH-S cells were established. After Bru intervention, Western blot/qPCR detected the expression of Nrf2, autophagy-, apoptosis-, and fibrosis-related proteins; HE/Masson staining assessed pathological damage; TEM analyzed autophagy levels in the lung tissue of silicosis mice and in AMs from silicosis patients; IF detected Nrf2 nuclear translocation and protein colocalization in MH-S cells.

In silicosis mouse lungs, Bru significantly reduced Nrf2 expression (↓37.74 %, p < 0.01) and nuclear translocation, decreased LC3-II/I and p62 levels (↓43.62 %, ↓28.71 %, p < 0.01), and restored LAMP2 (+72.50 %, p < 0.01) and autolysosome numbers. Cleaved-caspase3, Col-I, and α-SMA were also suppressed (↓23.25 %, ↓64.19 %, ↓16.00 %, p < 0.05), leading to alleviated apoptosis and fibrosis, with reduced collagen deposition and hydroxyproline content (↓23.54 %, ↓64.49 %, p < 0.01). qPCR results were consistent. In MH-S cells, similar trends were observed, while Nrf2 activation (Olt) produced opposite effects. IF further showed Bru inhibited Nrf2 nuclear translocation and reduced p62-Keap1 co-localization, indicating autophagy regulation via the Keap1-Nrf2-p62 pathway.

Bru restores autophagic degradation and reduces apoptosis, thereby attenuating pulmonary fibrosis. This study is the first to demonstrate that Bru exerts anti-fibrotic effects in silicosis by regulating autophagy via the Keap1-Nrf2-p62 pathway, providing novel mechanistic insights and therapeutic potential for silicosis.