Antifibrotic Effects of an α7 Nicotinic Acetylcholine Receptor Agonist in Keloid Fibroblasts and a Rat Scar Model

Abstract

Keloids are characterized by excessive extracellular matrix (ECM) accumulation and persistent inflammation, leading to disfiguring scars and poor therapeutic outcomes. The alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) has emerged as a key modulator of inflammatory and fibrotic signaling. This study evaluated the antifibrotic effects of tropisetron, a clinically available alpha 7nAChR agonist, in keloid fibroblasts (KFs) and a rat incisional scar model. In vitro, KFs exhibited reduced alpha 7nAChR expression, which was restored by tropisetron in a dose-dependent manner. Tropisetron treatment significantly decreased KF viability, downregulated pro-fibrotic genes (COL1A1, COL3A1, alpha-SMA), and upregulated matrix metalloproteinases (MMP1 and MMP3). Additionally, it suppressed phosphorylation of Smad2/3 and reduced expression of NF-kappa B and TNF-alpha, indicating inhibition of both TGF-beta and inflammatory pathways. In vivo, tropisetron-treated rats showed a similar to 40% reduction in scar area, improved collagen organization, and increased alpha 7nAChR expression in scar tissue. Western blot analysis confirmed decreased levels of collagen I, p-Smad2/3, alpha-SMA, NF-kappa B, and TNF-alpha. These results indicate that tropisetron exerts dual antifibrotic and anti-inflammatory effects through alpha 7nAChR-mediated signaling and enhanced ECM remodeling. This study provides the first evidence supporting alpha 7nAChR activation as a promising therapeutic strategy for managing keloids and other fibrotic skin disorders.