Bazedoxifene Targets gp130 Signaling to Suppress Fibroblast Activation in Pathological Cutaneous Fibrosis: Insights from Spatial Transcriptomics and scRNA-seq Data

Abstract

Pathological cutaneous fibrosis, exemplified by hypertrophic scarring and keloid formation, imposes substantial disease burden through persistent pruritus, pain and contracture-induced functional impairment. While the antifibrotic role of gp130 signaling inhibition has been established in visceral organ fibrosis, its therapeutic efficacy in pathological cutaneous fibrosis remains unexplored. Herein, we investigated the effectiveness of gp130 inhibition on cutaneous fibrosis by leveraging the application of Bazedoxifene, a clinically approved selective estrogen receptor modulator recently identified as a gp130 signaling inhibitor. We demonstrate that gp130 signaling is aberrantly activated in human keloid tissues and fibroblasts. In vitro, Bazedoxifene suppressed the fibroblast activation of disease-derived fibroblasts, featured by attenuated cell migration, myofibroblast differentiation and ECM production. In vivo, Bazedoxifene ameliorated dermal fibrosis and ECM deposition in both bleomycin-induced cutaneous fibrosis and keloid xenograft models. Notably, spatial transcriptomic analysis revealed reduced myofibroblast differentiation within fibrotic regions, providing tissue-level evidence for inhibition of fibroblast activation. Transcriptomic analysis revealed suppression of multiple fibrosis-associated signaling pathways following Bazedoxifene treatment, including the PI3K-AKT-mTOR, JAK-STAT, and MAPK pathways, with the PI3K-AKT-mTOR pathway showing the most prominent inhibition. Collectively, these findings establish Bazedoxifene repurposing as a promising therapeutic strategy for cutaneous fibrosis.