Targeting fPRDM16 to restore collagen phagocytosis: A mechanism to counteract the persistent fibrosis in aging lungs

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. 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. Fibroblasts from aged mice exhibited reduced collagen I phagocytosis, elevated lysosomal pH, and increased mtROS. Enhancing lysosomal function with mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) 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. 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. Schematic representation of the major signaling pathways involved in the impaired collagen I phagocytosis in fibroblasts as a result of decreased full-length PRD-BF1 and RIZ homology domain–containing 16 (fPRDM16) expression during aging. The schematic representation was drawn by Figdraw.