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

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

  • Biochem Pharmacol. 2025 Jul 19:241:117185. doi: 10.1016/j.bcp.2025.117185.
Yiming Qin 1,  Yifei Lu 2,  Peng Yang 2,  Weiming Gou 2,  Yujia Yang 1,  Fei Wang 1,  Meijuan Xie 1,  Han Wang 1,  Yunchao Zhang 1,  Gaoxing Luo 2,  Qing Zhang 3,  Xiaoyan Lyu 4
Affiliations

Affiliations

  • 1 Department of Dermatology and Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, PR China.
  • 2 Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Third Military Medical University (Army Medical University), Chongqing 400038, PR China.
  • 3 Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Third Military Medical University (Army Medical University), Chongqing 400038, PR China. Electronic address: zhangqing09@tmmu.edu.cn.
  • 4 Department of Dermatology and Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, PR China. Electronic address: lxiaoyan@scu.edu.cn.
PMID: 40692108 DOI: 10.1016/j.bcp.2025.117185
Abstract

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.

Keywords

Fibroblast; Fibrosis; Glycolysis; Morphea; Verteporfin; YAP1.

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