Mitophagy in idiopathic pulmonary fibrosis: from molecular mechanisms to therapeutic opportunities

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease with limited therapeutic options and a median survival of only 3–5 years. Although antifibrotic agents such as pirfenidone (PFD) and nintedanib can decelerate functional decline, they fail to reverse established fibrosis, underscoring an urgent need for novel therapeutic paradigms. Emerging evidence has positioned mitophagy—the selective autophagic clearance of damaged mitochondria—at the nexus of IPF pathogenesis. In this review, we systematically dissect the regulatory networks governing mitophagy, encompassing the canonical PINK1/Parkin pathway, receptor-mediated mechanisms (BNIP3/NIX/FUNDC1), and their intricate cross-talk with endoplasmic reticulum stress (ERS) and ferroptosis, highlighting how these interconnected pathways converge to determine alveolar epithelial cell (AEC) fate, fibroblast activation, and inflammatory reprogramming. Notably, the pathological impact of mitophagy is highly cell-type-specific and context-dependent, exhibiting protective functions in epithelial cells while paradoxically promoting pro-fibrotic phenotypes in macrophages under certain conditions, which poses both challenges and opportunities for therapeutic intervention. Furthermore, we critically evaluate emerging pharmacological and biological strategies targeting mitophagy, and propose that future combination regimens—guided by non-invasive mitophagy biomarkers—may overcome current clinical bottlenecks. By integrating mechanistic insights with translational perspectives, this review provides a roadmap for developing mitophagy-targeted interventions as a next-generation therapeutic paradigm for IPF.