Mitochondrial dysfunction in pulmonary fibrosis: from mechanisms to therapeutic opportunities

Pulmonary fibrosis (PF) is a progressive and often fatal interstitial lung disease characterized by excessive extracellular matrix deposition and irreversible remodeling of lung architecture. Although current antifibrotic therapies can slow disease progression, they remain unable to halt or reverse fibrosis, underscoring the need for a deeper mechanistic understanding and new therapeutic strategies. Mitochondria are increasingly recognized as central regulators of PF pathogenesis, extending beyond their canonical role in energy production. Emerging evidence indicates that mitochondrial dysfunction contributes to epithelial injury, fibroblast activation, immune dysregulation, and the persistence of a profibrotic microenvironment. Alterations in mitochondrial biogenesis, dynamics, mitophagy, redox homeostasis, and oxidative phosphorylation constitute interconnected processes that converge on mitochondrial quality control (MQC) failure. These defects may establish self-amplifying pathogenic circuits that sustain fibrotic progression. Notably, mitochondrial dysfunction in PF shows clear cell type-dependent features, supporting the concept that mitochondrial dysregulation operates within a multicellular network rather than as an isolated cellular defect. Therapeutically, targeting mitochondrial pathways-including enhancement of biogenesis, correction of dynamic imbalance, restoration of mitophagy, and redox modulation-has demonstrated antifibrotic potential in experimental models. However, key questions remain regarding causality, stage-specific roles, and the long-term safety of mitochondrial modulation. This review summarizes recent advances in understanding mitochondrial dysfunction in PF, highlights its integration across metabolic and signaling networks, and discusses emerging mitochondria-targeted interventions. A systems-level perspective on mitochondrial quality control may help refine future research directions and support the development of more precise antifibrotic therapies.