Mycophenolate mofetil inhibits ferroptosis by boosting autophagy to prevent pulmonary fibrosis

Pulmonary fibrosis is a chronic, progressive interstitial lung disease with few effective treatments. This study investigates the therapeutic effects and mechanisms of mycophenolate mofetil (MMF) in treating pulmonary fibrosis. Pulmonary fibrosis models were developed using mice treated with bleomycin and MRC-5 cells treated with TGF-β1. The anti-fibrotic effects of MMF were assessed using Micro-CT imaging, lung function analysis, and histological staining methods such as H&E and Masson. The mechanisms of action were elucidated using RNA fluorescence in situ hybridization, co-immunoprecipitation, RNA immunoprecipitation, RNA sequencing, and half-life experiments. The findings demonstrated that MMF effectively inhibited fibroblast activation and the proliferation and migration of myofibroblasts. It impeded the nucleocytoplasmic translocation of human antigen R (HuR) and facilitated its degradation by decreasing circFOXP1 levels. This downregulation reduced HuR target gene expression, thus promoting autophagy. The upregulation of autophagy inhibited the interaction between SLC7A11 and LC3-II and its localization to lysosomes, thereby preventing the degradation of SLC7A11. This process led to an increase in GPX4 expression and a reduction in iron ion concentrations, ultimately suppressing ferroptosis. MMF can alleviate pulmonary fibrosis by modulating the interplay between autophagy and ferroptosis, indicating its potential as a candidate drug and therapeutic target for pulmonary fibrosis treatment.