Targeting YAP1-dependent aerobic glycolysis to mitigate fibrosis progression in morphea.

Morphea, a rare autoimmune disorder characterized by progressive skin fibrosis and soft tissue atrophy, remains clinically challenging due to poorly understood pathogenesis. Here, we revealed that mechanical abnormalities in morphea tissues activate the transcriptional co-activator Yes-associated protein 1 (YAP1), which drives pathological fibrosis through glycolytic reprogramming. Mechanistically, YAP1 promotes glycolysis by upregulating the expression of phosphofructokinase platelet type (PFKP), thus creating a self-reinforcing profibrotic cycle. Consequently, pharmacological inhibition of YAP1 with verteporfin (VP) significantly suppressed both transforming growth factor-beta 1 (TGF-β1)-induced glycolysis and fibrotic responses in vitro, while alleviating bleomycin-induced cutaneous fibrosis in murine models. Notably, VP demonstrated mitochondrial protective effects through dual modulation of fission machinery and PGC1α-mediated biogenesis pathway, further confirming its role in metabolic regulation. Collectively, these findings elucidate that YAP1-mediated metabolic dysregulation drives morphea progression and suggest that targeting YAP1 to modulate metabolic reprogramming represents a promising therapeutic strategy for this disease.