A study published recently in Current Molecular Pharmacology has uncovered a key mechanism linking aging to persistent pulmonary fibrosis, identifying the transcriptional regulator fPRDM16 as a potential therapeutic target. Led by Jun Peng and corresponding author Ying Meng from Nanfang Hospital, Southern Medical University, the research demonstrates that natural aging impairs the resolution of bleomycin-induced lung fibrosis in mice, largely due to a decline in the ability of lung fibroblasts to clear collagen via phagocytosis.
The team found that fibroblasts from aged mice exhibited reduced collagen I phagocytosis, elevated lysosomal pH, and increased mitochondrial reactive oxygen species (mitoROS). Mechanistically, they identified a pathogenic feedback loop between lysosomal dysfunction and mitochondrial oxidative stress, which is exacerbated by the downregulation of full-length PRDM16 (fPRDM16) with age and upon TGF-β stimulation. Notably, enhancing lysosomal function with rapamycin or scavenging mitoROS with mitoquinone restored phagocytic capacity. Furthermore, overexpression of fPRDM16 rescued phagocytic defects, improved lysosomal acidification, and stabilized antioxidant responses, effectively breaking the vicious cycle. "Our findings suggest that restoring youthful levels of collagen phagocytosis in fibroblasts may serve as a promising therapeutic approach for pulmonary fibrosis," said corresponding author Ying Meng. In vivo, aged mice showed impaired fibrosis resolution and reduced lung fPRDM16 levels, corroborating the cellular data.
