Silica-induced ferroptosis activates retinoic acid signaling in dendritic cells to drive inflammation and fibrosis in silicosis.

Silicosis, a chronic lung disease caused by inhalation of silica (SiO2) particles from environmental contamination or industrial exposure, is characterized by persistent inflammation and fibrosis. This study elucidates a novel mechanism where SiO2 exposure triggers ferroptosis, a lipid peroxidation-dependent form of cell death, in dendritic cells (DCs), thereby activating retinoic acid (RA) signaling. The RA response amplifies inflammatory pathways, including cGAS-STING-IFN-I and IL-1β signaling, exacerbating lung inflammation and fibrosis. The study uses murine models to demonstrate that ferroptosis inhibitors, such as ferrostatin-1, mitigate SiO2-induced inflammation and collagen deposition. Furthermore, systemic administration of the synthetic retinoid AM80 reduces pulmonary damage by modulating immune cell distribution and promoting lymphocyte homing. These findings reveal the interplay between ferroptosis and RA signaling as a pivotal driver of silicosis pathology and suggest therapeutic avenues targeting ferroptosis and RA modulation for disease management.