Objective: Long-term inhalation of silica dust particles leads to lung tissue fibrosis, resulting in impaired gas exchange and increased mortality. Silica inhalation triggers the aging of epithelial cells (AECs), which is a key contributor to the development of pulmonary fibrosis. Myricetin, a flavonoid compound extracted from Myrica genus plants, possesses various biological activities, including antioxidant and immunomodulatory effects. However, the mechanisms underlying myricetin's ability to counter senescence and fibrosis need to be further studied. Experimental approach: In vivo, the antifibrotic and anti-senescence effects of myricetin were evaluated using a silica-induced pulmonary fibrosis mouse model. To further elucidate the mechanisms by which myricetin counteracts silica-induced senescence, in vitro experiments were conducted using AECs. Results: Our studies revealed that myricetin treatment alleviated silica-induced mortality, improved lung function, and reduced the severity of pulmonary fibrosis in mice. Immunofluorescence analysis suggests its potential in mitigating senescence of AECs. Under laboratory conditions, myricetin intervened in the cellular senescence pathway induced by silica dust by modulating mitochondrial function. It acted through the PPARγ−PGC1α axis, effectively reducing silica-induced mitochondrial oxidative stress in AECs, promoting mitophagy, and maintaining mitochondrial dynamics. However, the efficacy of myricetin was reversed under PPARγ siRNA intervention. Additionally, myricetin exhibited an enhancing effect on PPARγ and autophagy in animal models. Treatment with PPARγ and PGC-1α siRNA elucidated the role of myricetin in promoting the formation of a positive feedback loop between PPARγ and PGC-1α. Additionally, the PPARγ inhibitor GW9662 verified the in vivo effects of myricetin. Conclusions: Myricetin activates PPARγ, forming a PPARγ−PGC-1α loop, which promotes mitophagy and maintains mitochondrial dynamics. This alleviates epithelial cell senescence induced by silica exposure, consequently mitigating silica-induced pulmonary fibrosis in mice.
