Acetoacetate ameliorates skin fibrosis by modulating TGF-β1–Smad2/3 signaling pathway

Skin fibrosis is a progressive pathologic outcome of prolonged healing of cutaneous wounds, which has been well accepted as a metabolic disease in a recent study. However, the impact of ketone body metabolism on the development of cutaneous fibrosis remains largely unknown. Here, we found that ketone body metabolism was impaired in both human scars and bleomycin (BLM)-induced skin fibrogenesis of mice by bioinformatics analysis, which was further evidenced by downregulated expression of key modulators of ketone metabolism, including BDH1 (3-hydroxybutyrate dehydrogenase 1), OXCT1 (3-oxoacid CoA-transferase 1), and ACAT1 (acetyl-CoA acetyltransferase 1). With knockdown of OXCT1, a spontaneous onset of fibrosis in normal skin and exacerbation of BLM-induced skin fibrogenesis were observed. In dermal fibroblasts treated with transforming growth factor-beta 1, knockdown of OXCT1 improved their phenotype transition to myofibroblasts. Mechanistic studies indicated that phosphorylation of Smad2/3 signaling was markedly suppressed by acetoacetate supplementation. More importantly, we found that local administration remarkably alleviated fibrosis of BLM-treated skin in mice. Thus, our findings underscore the therapeutic potential of acetoacetate as an alternative intervention for skin fibrosis.