Mitophagy in Pulmonary Fibrosis: Molecular Interactions, HypoxiaInteractions, and Therapeutic Strategies

Mitophagy plays a central role in the pathogenesis of Pulmonary Fibrosis (PF). Defective mitophagy leads to the accumulation of damaged mitochondria, resulting in bursts of mitochondrial Reactive Oxygen Species (mtROS), ferroptosis, and cellular senescence. These processes collectively promote aberrant fibroblast activation and excessive extracellular matrix deposition. This review systematically explored the molecular regulatory network of mitophagy in PF and its interactions with hypoxia-responsive pathways. These abnormalities create a vicious cycle of autophagy inhibition and fibrosis activation, which accelerates disease progression. Regarding therapeutic strategies, various small-molecule drugs and natural compounds have shown anti-fibrotic potential by activating mitophagy, alleviating oxidative stress, and delaying cellular senescence. Emerging technologies, such as gene therapy, nanocarriers, and combination therapies, are providing additional avenues for clinical translation. However, targeting mitophagy still faces challenges, including cell type specificity, dynamic conversion thresholds, and delivery efficiency. Future efforts will require integrating single-cell multi-omics and artificial intelligence approaches to develop spatiotemporally precise intervention systems for personalized, precision treatment of PF.