Prophylactic quercetin administration attenuates pulmonary fibrosis via ferroptosis-resistant priming of alveolar epithelial cells.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) carries high mortality and short survival, presenting significant clinical challenges. Current treatments primarily target to mitigate IPF progression, with insufficient focus on prevention. METHODS: We established bleomycin (BLM)-induced IPF model in mice and alveolar epithelial cells. Quercetin (QUE) was administered under two mutually exclusive dosing windows: preventive (pre-BLM only) and therapeutic (post-BLM only). RESULTS: Prophylactic QUE administration in mice prior to BLM challenge achieved fibrosis reduction comparable to post-injury treatment, while better mitigating peaks of epithelial damage, ferroptosis, and senescence. The preventive regimen also accelerated GSH and GPx4 recovery. Mechanistically, QUE triggers adaptive stress in healthy alveolar epithelial cells, evidenced by mild ROS elevation and oxidative stress response pathway activation. This adaptive stress minimally impacts cellular viability, proliferation, clonogenicity, apoptosis, or senescence in healthy cells. Instead, it primes 14-3-3γ-mediated phosphorylation to enhance NRF2 nuclear translocation, driving sustained elevation of GSH and GPx4 and conferring ferroptosis resistance, thereby limiting fibrogenesis. Crucially, co-administration of Mito-TEMPO or Z-VAD-FMK suppressed QUE-induced ROS but concurrently abolished prevention against BLM injury, confirming preconditioning via adaptive stress as the core mechanism. CONCLUSIONS: Our findings unveil QUE as a promising preventive agent against IPF, mediated through alveolar epithelial preconditioning to enhance ferroptosis resistance.