Targeting Fprdm16 to Restore Collagen Phagocytosis: A Mechanism to Counteract the Persistent Fibrosis in Aging Lungs

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 (mitoROS) were assessed. The role of full-length PRD-BF1 and RIZ homology (PR) domain-containing 16 (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 mitoROS. Enhancing lysosomal function with rapamycin or scavenging mitoROS with mitoquinone restored phagocytosis. fPRDM16 expression was downregulated with age and upon transforming growth factor-j3 (TGF-j3) stimulation. Its overexpression rescued phagocytic defects, improved lysosomal acidification, and reduced mitoROS, 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.