The amphiregulin-epidermal growth factor receptor axis drives fibroblast activation to promote keloid progression.

Abstract

Background: Keloids represent a prevalent form of pathological scarring, yet their treatment remains highly challenging in clinical practice. The pathogenesis of keloids remains incompletely understood.

Objectives: To investigate the function and mechanism of amphiregulin (AREG) in keloids.

Methods: We performed transcriptomic profiling of keloid fibroblasts (KFs) and normal fibroblasts (NFs). Keloid skin explants and keloid-bearing nude mice were used to explore the roles of AREG in keloids.

Results: AREG was upregulated in keloids and associated with disease severity. In vitro recombinant AREG promoted proliferation, migration and extracellular matrix (ECM) production in KFs. We further demonstrated that AREG signalling mediates keloid fibroblast activation through the epidermal growth factor receptor (EGFR). In addition, we revealed that the MAPK signalling pathway functions as a key downstream effector of the AREG-EGFR axis. As an EGFR antagonist, gefitinib effectively reduced ECM component deposition in both keloid skin explants and a nude mouse xenograft model.

Conclusions: These results not only highlight the role of AREG in driving keloid progression but also point to the translational relevance of gefitinib as a viable therapeutic candidate for keloids.