Targeting the Epigenetic Regulator CBX5 Promotes Fibroblast Metabolic Reprogramming and Inhibits Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here we show that the epigenetic regulator chromobox protein homolog 5 (CBX5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including Cthrc1, Col1a1, and Spp1, and by the upregulation of metabolic genes with anti-fibrotic activity such as Ppara and Pparg. scRNA-seq and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-seq analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited TGF-beta-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, we showed that inhibition of the CBX5 pathway in IPF fibroblasts synergistically potentiated metformin-induced AMPK activation and IPF fibroblast quiescence. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.