Roh Hyun, Kim Yo Han, Heo Kyung Jun, Hong Jong Won, Lee Won Jai
Department of Plastic and Reconstructive Surgery, Yonsei University, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea.
Int J Mol Sci. 2025 Sep 11;26(18):8868. doi: 10.3390/ijms26188868.
Keloids are characterized by excessive extracellular matrix (ECM) accumulation and persistent inflammation, leading to disfiguring scars and poor therapeutic outcomes. The α7 nicotinic acetylcholine receptor (α7nAChR) has emerged as a key modulator of inflammatory and fibrotic signaling. This study evaluated the antifibrotic effects of tropisetron, a clinically available α7nAChR agonist, in keloid fibroblasts (KFs) and a rat incisional scar model. In vitro, KFs exhibited reduced α7nAChR expression, which was restored by tropisetron in a dose-dependent manner. Tropisetron treatment significantly decreased KF viability, downregulated pro-fibrotic genes (COL1A1, COL3A1, α-SMA), and upregulated matrix metalloproteinases (MMP1 and MMP3). Additionally, it suppressed phosphorylation of Smad2/3 and reduced expression of NF-κB and TNF-α, indicating inhibition of both TGF-β and inflammatory pathways. In vivo, tropisetron-treated rats showed a ~40% reduction in scar area, improved collagen organization, and increased α7nAChR expression in scar tissue. Western blot analysis confirmed decreased levels of collagen I, p-Smad2/3, α-SMA, NF-κB, and TNF-α. These results indicate that tropisetron exerts dual antifibrotic and anti-inflammatory effects through α7nAChR-mediated signaling and enhanced ECM remodeling. This study provides the first evidence supporting α7nAChR activation as a promising therapeutic strategy for managing keloids and other fibrotic skin disorders.
瘢痕疙瘩的特征是细胞外基质（ECM）过度积聚和持续炎症，导致毁容性瘢痕和治疗效果不佳。α7烟碱型乙酰胆碱受体（α7nAChR）已成为炎症和纤维化信号传导的关键调节因子。本研究评估了临床可用的α7nAChR激动剂托烷司琼在瘢痕疙瘩成纤维细胞（KFs）和大鼠切口瘢痕模型中的抗纤维化作用。在体外，KFs表现出α7nAChR表达降低，托烷司琼以剂量依赖性方式使其恢复。托烷司琼治疗显著降低了KF的活力，下调了促纤维化基因（COL1A1、COL3A1、α-SMA），并上调了基质金属蛋白酶（MMP1和MMP3）。此外，它抑制了Smad2/3的磷酸化，降低了NF-κB和TNF-α的表达，表明对TGF-β和炎症途径均有抑制作用。在体内，接受托烷司琼治疗的大鼠瘢痕面积减少了约40%，胶原组织得到改善，瘢痕组织中α7nAChR表达增加。蛋白质印迹分析证实胶原蛋白I、p-Smad2/3、α-SMA、NF-κB和TNF-α的水平降低。这些结果表明，托烷司琼通过α7nAChR介导的信号传导发挥双重抗纤维化和抗炎作用，并增强了ECM重塑。本研究提供了首个证据，支持激活α�nAChR作为治疗瘢痕疙瘩和其他纤维化皮肤病的一种有前景的治疗策略。
