Estrogen signaling processes in fibroblasts: a scoping review

Fibroblasts are a heterogeneous cell population with distinct functions, known to respond to estrogens through nuclear estrogen receptor alpha and beta (ERα, ERβ), and the membrane G protein-coupled estrogen receptor (GPER). In this scoping review, we systematically mapped the current evidence on the contribution of estrogen, phytoestrogens, and selective estrogen receptor modulators (SERMs) on estrogen signaling in fibroblasts. A systematic search across PubMed, Scopus and EMBASE was conducted, followed by screening of titles/abstracts, and full text in Covidence, resulting in 67 eligible studies. Our findings reveal that fibroblasts respond to estradiol (E2), phytoestrogens, and SERMs, activating both genomic and non-genomic responses through ERα, ERβ and GPER. These responses contribute to anti-fibrosis, wound healing, anti-inflammatory, and protective effects across diverse fibroblast models. In contrast, in cancer-associated fibroblasts, these ligands can promote cancer in a paracrine manner, emphasizing the role of the tumor microenvironment in cancer progression. However, significant gaps including small sample sizes, high ligand concentrations, lack of mechanistic detail and limited investigation of sex-specific fibroblast responses remain. Addressing these gaps by standardized experimental designs, physiologically relevant models, clearer distinction of receptor-specific pathways and sex-specific analyses in future research will advance the understanding of estrogen-mediated fibroblast signaling and aid in the development of novel therapeutic targets for estrogen-related disorders.