Resveratrol inhibits hypertrophic scars formation by activating autophagy via the miR-4654/Rheb axis

Abstract

Hypertrophic scars (HSs) are a type of pathological scar which are induced by surgery, burn injuries or trauma during the healing process. due to the high recurrence rates and strong invasive properties, HSs have become a major clinical issue. Resveratrol has been identified as a potential agent to suppress scar formation; however, the underlying mechanism of action remains unclear. Therefore, the present study aimed to investigate the effect of resveratrol on HS-derived fibroblasts (HSFBs) in vitro. MTT assay was performed to evaluate cell viability following the resveratrol treatment. Western blot and rT-qPcr analysis was used to identify the expression levels and the relationship among autophagic markers, mir-4654 and resveratrol treatment. Finally, GFP-lc3 stable HSFBs cells were generated to further assess the effect of resveratrol. The results revealed that resveratrol significantly induced cell death in a dose-dependent manner and induced autophagy by downregulating the expression levels of rheb in HSFBs. notably, microRNA-4654 (miR-4654) was significantly decreased in the HSFBs and re-upregulated by resveratrol treatment dose-dependently. Through the bioinformatic analysis and luciferase assay, mir-4654 was identified to directly target rheb. Transfection studies showed that mir-4654 negative correlated with rheb expression, suggesting that the autophagic process may be altered by the mir-4654/rheb axis under the control of resveratrol. in conclusion, the results of the present study suggested that resveratrol may promote autophagy by upregulating mir-4654, which in turn may suppress rheb expression via directly binding to the 3'-untranslated region of Rheb. These findings provided a novel insight into the development of potential therapeutic targets for HSs.