Exploring the Complexities of TGF-β Signaling in Keloids: Beyond the Classical Smad Pathway
Year: 2026
Type: article
Abstract: Keloid is a benign skin disease with excessive growth of fibroblasts, characterized by too much abnormal extracellular matrix deposited in the dermis. It is generally believed that transforming growth factor-β (TGF-β) is the core cytokine that causes keloid. Previously, it was thought that its pathogenic effect was mainly attributed to the classical Smad-dependent pathway. It directly shuttles signals to the nucleus to trigger pro-fibrotic gene transcription. However, accumulating evidence now points to the equally vital role of Smad-independent signaling. Unlike the direct nuclear translocation of Smads, these alternative pathways transmit signals through rapid intracellular kinase cascades. They jointly direct the proliferation, migration, anti-apoptosis, fibrogenesis, and chronic inflammation of fibroblasts in keloids. This review attempts to comprehensively clarify the molecular processes regulated by TGF-β through non-Smad pathways (such as MAPK, PI3K/Akt, Rho GTPase, Wnt/β-catenin, JAK/STAT). Translating these non-Smad insights helps to overcome the high recurrence rates of traditional therapies. Targeting these specific molecular hubs through combination and precision therapies serves to reprogram the fibrotic microenvironment.
DOI: 10.3390/ijms27083600
Institutions: Sichuan University, West China Hospital of Sichuan University
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7154693137