Cholesterol orchestrates skin fibrosis via the CH25H-CYP7B1-SMAD2/3 axis

Skin fibrosis is a pathological condition characterized by excessive deposition of extracellular matrix (ECM) components, primarily collagen, which leads to compromised tissue function. Although skin fibrosis is currently considered to be associated with metabolic disorders, the role of cholesterol metabolism in the pathogenesis of skin fibrosis has not been fully elucidated. scRNA-seq and RNA-seq analyses revealed that key modulators involved in cholesterol metabolism, such as lectin-type oxidized low-density lipoprotein receptor 1 (LOX1), cholesterol 25-hydroxylase (CH25H), and 25-hydroxycholesterol 7α-hydroxylase (CYP7B1), were upregulated in human keloid samples. Mendelian randomization (MR) analysis demonstrated a causal relationship between cholesterol levels and dermal fibrosis. We further confirmed that cholesterol levels were elevated in fibrotic skin and were positively correlated with the severity of fibrosis. Moreover, the subcutaneous injection of cholesterol significantly increased the expression of fibrotic indicators, including Col1a1 , Col3a1 , Fn1 , and α-SMA , and promoted both spontaneous and bleomycin (BLM)-induced skin fibrosis. Notably, this cholesterol-induced increase in the expression of phospho-Smad2/3 and fibrotic indicators was significantly attenuated when Ch25h was knocked down. Furthermore, the administration of tauroursodeoxycholic acid (TUDCA), which promotes cholesterol efflux, resulted in a remarkable reduction in intracellular cholesterol levels and ameliorated skin fibrosis in BLM-induced mice. Our results demonstrate that the CH25H-CYP7B1-SMAD2/3 axis is crucial in the pathogenesis of skin fibrosis. TUDCA treatment reduced cholesterol accumulation and mitigated the progression of skin fibrosis, providing a promising therapeutic strategy.