Acetoacetate Ameliorates Skin Fibrosis by Modulating TGF-β1/Smad2/3 Signaling Pathway

Skin fibrosis is a progressive pathologic outcome of prolonged healing of cutaneous wound which has been well accepted as a metabolic disease in 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 induced skin fibrogenesis of mouse by bioinformatics analysis, which was further evidenced by downregulated expression of key modulators of ketone metabolism including BDH1, OXCT1, and ACAT1. With knockdown of OXCT1, a spontaneous onset of fibrosis in normal skin and exacerbation of bleomycin induced skin fibrogenesis was observed. In dermal fibroblasts treated with TGF-β1, knockdown of OXCT1 improved their phenotype transition to myofibroblasts. Mechanistic studies indicated that phosphorylation of Smad2/3 signaling was markedly suppressed by acetoacetate (AcAc) supplementation. More importantly, we found that local administration remarkably alleviated fibrosis of bleomycin treated skin in mouse. Thus, our findings underscore the therapeutic potential of AcAc as an alternative intervention for skin fibrosis.