Double-edged mitophagy: balancing inflammation and resolution in lung disease

Inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and asthma, are driven by mitochondrial dysfunction and aberrant immune responses, yet the regulatory role of mitophagy-a selective autophagy eliminating damaged mitochondria-remains poorly defined. This review synthesizes evidence from in vivo and in vitro studies to dissect the molecular interplay between mitophagy and inflammation. Key fundings reveal that mitophagy exerts context-dependent effects: Protective mitophagy (via PTEN-induced putative kinase 1 [PINK1]-Parkin or FUN14 domain-containing protein 1 [FUNDC1] pathways) clears mitochondrial reactive oxygen species (mtROS)/mitochondrial DNA (mtDNA), suppressing NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and pyroptosis, but excessive mitophagy exacerbates mitochondrial fragmentation and necroptosis. Notably, bidirectional cross-talk exists, and therapeutic strategies-genetic and pharmacological-could restore mitophagy flux, attenuating inflammation in preclinical models. However, challenges persist in targeting tissue-specific mitophagy (such as alveolar and bronchial epithelia). This work underscores mitophagy as a double-edged sword in lung inflammation and proposes precision interventions to balance mitochondrial quality control, offering novel avenues for inflammatory lung diseases.