Circular RNA HECTD1 knockdown inhibits transforming growth factor-beta/small mothers against decapentaplegic (TGF-beta/Smad) signaling to reduce hypertrophic scar fibrosis

Scars are nearly impossible to avoid after a skin injury, but despite advancements in the treatment modalities, they remain a clinical problem, especially hypertrophic scars (HS). Many studies include the mechanism of formation and inhibition of HS, but it is not fully understood yet. Circular RNA HECTD1 (circHECTD1), for the first time, has been found to have roles in HS physiology. We determined the relative circHECTD1 levels in HS fibrous cells and tissues by RT-qPCR. Afterward, the effect of circHECTD1 knockdown on the proliferation, migration, invasion, fibrosis, and Transforming Growth Factor-beta/small mothers against decapentaplegic (TGF-beta/Smad) signaling was studied using CCK-8, wound healing, Transwell, and western blot assays. After the role of circHECTD1 was clarified, its targeted micro RNA (miR) was predicted using the Starbase database, and we constructed a miR-142-3p mimic to study the details of its regulation mechanism. We used the TargetScan database to predict the downstream target high mobility group box 1 (HMGB1) of miR-142-3p, and the luciferase report assay verified the binding, and then its effect was determined by RT-qPCR. circHECTD1 is highly expressed in HS tissues and human skin hypertrophic scar fibroblasts (HSF); its loss of function inhibits cell proliferation, migration, invasion, fibrosis, and TGF-beta/Smad signaling. However, miR-142-3p inhibitor reverses the effect of circHECTD1 on all the above-mentioned aspects, including HMGB1 expression. In conclusion, circHECTD1 knockdown interrupts TGF-beta/Smad signaling through miR-142-3p/HMGB1 and suppresses scar fibrosis.