Study identifies fPRDM16 as target for age-related pulmonary fibrosis

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.

The study also analyzed public transcriptomic datasets, revealing that PRDM16 is significantly downregulated in IPF patients and is positively correlated with pathways involved in ECM degradation and negative regulation of oxidative stress.

Ying Meng, Nanfang Hospital, Southern Medical UniversityTherapeutic strategies aimed at enhancing PRDM16 expression or function may offer a promising approach to reverse persistent fibrosis by restoring the innate collagen-clearing capacity of lung fibroblasts."

While further in vivo validation and clinical studies are needed, this work establishes fPRDM16 as a novel and precision target for counteracting age-related fibrotic persistence.

Source:

FAR Publishing Limited

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