Mechanical pressure-induced dedifferentiation of myofibroblasts inhibits scarring via SMYD3/ITGBL1 signaling.

Pressure therapy (PT) is an effective intervention for reducing scarring, but its underlying mechanism remains largely unclear. Here, we demonstrate that human scar-derived myofibroblasts dedifferentiate into normal fibroblasts in response to PT, and we identify how SMYD3/ITGBL1 contributes to the nuclear relay of mechanical signals. In clinical specimens, reductions in SMYD3 and ITGBL1 expression levels are strongly associated with the anti-scarring effects of PT. The integrin β1/ILK pathway is inhibited in scar-derived myofibroblasts upon PT, leading to decreased TCF-4 and subsequently to reductions in SMYD3 expression, which reduces the levels of H3K4 trimethylation (H3K4me3) and further suppresses ITGBL1 expression, resulting the dedifferentiation of myofibroblasts into fibroblasts. In animal models, blocking SMYD3 expression results in reductions of scarring, mimicking the positive effects of PT. Our results show that SMYD3 and ITGBL1 act as sensors and mediators of mechanical pressure to inhibit the progression of fibrogenesis and provide therapeutic targets for fibrotic diseases.