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 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.