Cheng Xinwei, Gao Zhen, Zhang Jin, Zheng Hongkun, Shan Shengzhou, Zhou Jia
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, China.
Int J Biol Sci. 2025 Jan 1;21(2):658-670. doi: 10.7150/ijbs.104484. eCollection 2025.
Skin fibrotic diseases are characterized by abnormal fibroblast function and excessive deposition of extracellular matrix. Our previous single-cell sequencing results identified an enriched fibroblast subcluster in skin fibrotic tissues that highly expresses the actin cross-linking cytoskeletal protein Transgelin (TAGLN), which bridges the mechanical environment of tissues and cellular metabolism. Therefore, we aimed to investigate the role of TAGLN in the pathogenesis of skin fibrosis. Transwell, wound healing, collagen gel contraction assay, immunofluorescence and RNA-seq analyses were used to validate and explore the potential mechanisms of the TAGLN-RhoA/ROCK2-SLC2A3-mediated mechano-metabolic axis in dermal fibrosis. The therapeutic efficacy of targeting TAGLN was validated using a bleomycin-induced mouse model of skin fibrosis. Functional assays revealed that downregulation of TAGLN inhibited motility and secretory function of fibroblasts, including invasion, migration, contraction, and collagen secretion. The glucose carrier SLC2A3 was identified as one of the downstream targets of TAGLN by RNA-sequencing analysis and further validation. We further demonstrated that TAGLN regulates the expression of SLC2A3 through the RhoA/ROCK2 pathway, a key pathway of mechanotransduction, thereby affecting glycolysis and motility of fibroblasts. This study reveals the existence of the TAGLN-RhoA/ROCK2-SLC2A3 mechano-metabolic axis in skin fibrotic diseases and provides a promising target for its clinical treatment.
皮肤纤维化疾病的特征是成纤维细胞功能异常和细胞外基质过度沉积。我们之前的单细胞测序结果在皮肤纤维化组织中鉴定出一个富集的成纤维细胞亚群，该亚群高度表达肌动蛋白交联细胞骨架蛋白转胶蛋白（TAGLN），它连接组织的力学环境和细胞代谢。因此，我们旨在研究TAGLN在皮肤纤维化发病机制中的作用。采用Transwell实验、伤口愈合实验、胶原凝胶收缩实验、免疫荧光和RNA测序分析来验证和探索TAGLN-RhoA/ROCK2-SLC2A3介导的机械代谢轴在皮肤纤维化中的潜在机制。使用博来霉素诱导的皮肤纤维化小鼠模型验证了靶向TAGLN的治疗效果。功能实验表明，TAGLN的下调抑制了成纤维细胞的运动和分泌功能，包括侵袭、迁移、收缩和胶原分泌。通过RNA测序分析和进一步验证，葡萄糖载体SLC2A3被确定为TAGLN的下游靶点之一。我们进一步证明，TAGLN通过机械转导的关键途径RhoA/ROCK2途径调节SLC2A3的表达，从而影响成纤维细胞的糖酵解和运动。本研究揭示了皮肤纤维化疾病中TAGLN-RhoA/ROCK2-SLC2A3机械代谢轴的存在，并为其临床治疗提供了一个有前景的靶点。
