Abstract

Background Aging impairs the resolution of bleomycin-induced pulmonary fibrosis (PF) in mice. As extracellular matrix degradation is crucial for PF reversal, we investigated whether aging compromises collagen I phagocytosis and explored the underlying mechanisms. Methods Primary lung fibroblasts were isolated from young (6-week-old) and middle-aged (8-month-old) mice. Collagen I phagocytosis, lysosomal pH, and mitochondrial reactive oxygen species (mtROS) were assessed. The role of fPRDM16 was evaluated via overexpression and knockdown. In vivo fibrosis resolution and fPRDM16 expression were analyzed in bleomycin-treated mice. Results Fibroblasts from aged mice exhibited reduced collagen I phagocytosis, elevated lysosomal pH, and increased mtROS. Enhancing lysosomal function with rapamycin or scavenging mtROS with mitoquinone restored phagocytosis. fPRDM16 expression was downregulated with age and upon TGF-β stimulation. Its overexpression rescued phagocytic defects, improved lysosomal acidification, and reduced mtROS, thereby disrupting a pathogenic mitochondria-lysosome feedback loop. In vivo, aged mice showed impaired fibrosis resolution and reduced lung fPRDM16 levels. Conclusions fPRDM16 downregulation in aging impairs fibroblast-mediated collagen clearance via a mitochondria-lysosome dysfunction loop. Targeting fPRDM16 may represent a novel therapeutic strategy to promote fibrosis resolution.