Collagen Receptor DDR1 Drives Fibroblast Proliferation in Hyperplastic Scarring

Hypertrophic scar (HS) is characterised by excessive fibroblast proliferation and abnormal differentiation; however, the underlying molecular mechanisms remain incompletely understood. Here, we identify the collagen receptor discoidin domain receptor 1 (DDR1) as a key regulator of fibroblast activation during HS formation. We observed markedly increased expression and phosphorylation of DDR1 in human HS tissues compared with adjacent normal skin. To investigate the functional role of DDR1, primary fibroblasts derived from human HS tissues were stimulated with collagen III to induce DDR1 activation in vitro. DDR1 activation significantly enhanced fibroblast proliferation and promoted myofibroblast differentiation, as evidenced by increased collagen III and α-smooth muscle actin (α-SMA) expression. Concomitantly, DDR1 activation suppressed the expression of the tumour suppressor phosphatase and tensin homologue (PTEN) and promoted nuclear translocation of NF-κB p65, a known inhibitor of PTEN transcription. Consistent with these findings, HS tissues exhibited elevated DDR1 expression and reduced PTEN levels relative to adjacent normal skin. The pathological role of DDR1 in HS was further validated in a rabbit ear model, in which local administration of a selective DDR1 inhibitor significantly attenuated scar formation. Together, these findings delineated a collagen III-DDR1-PTEN signalling axis that drives fibroblast proliferation and activation in hypertrophic scarring, highlighting DDR1 as a promising therapeutic target for the prevention and treatment of HS.