Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism.

Skin fibrosis, characterized by uncontrolled secretion of extracellular matrix (ECM) proteins such as collagen, can lead to excessive scarring and compromised tissue function. Despite the widespread occurrence of fibrotic diseases, effective therapies are lacking. Recent clinical studies have demonstrated a positive correlation between serum homocysteine (Hcy) levels and the severity of systemic sclerosis. However, it remains unclear whether Hcy accumulation plays a pathogenic role in skin fibrosis. Here, we report that Hcy metabolism in fibroblasts plays a crucial role in regulating the pathogenesis of skin fibrosis. Fibrotic skin fibroblasts exhibited elevated levels of Hcy due to the downregulation of catabolism genes CBS and MTR. Experimental skin fibrosis was induced and exacerbated in mouse skin fibroblasts and tissues through adenoviral knockdown of Cbs or Mtr, whereas overexpression of these catabolic genes mitigated the pathogenesis. Furthermore, exogenous Hcy supplementation induced and aggravated the expression of inflammatory and fibrotic genes, promoting both spontaneous and BLM-induced skin fibrosis. Notably, folate administration enhanced Hcy catabolism and ameliorated skin inflammation and fibrosis by inhibiting JAK2/STAT3 signaling pathway. Collectively, these results indicate that skin fibrosis is associated with Hcy metabolic disorders and suggest that targeting Hcy metabolism or supplementing folate may provide a novel strategy for skin fibrosis.