Dioscin improves hypertrophic scars by inducing apoptosis and ferroptosis of scar fibroblasts through mitochondrial oxidative stress damage.

Hypertrophic scar (HS) is a common fibrotic disease primarily caused by excessive activation and proliferation of fibroblasts. Dioscin, a steroidal saponin isolated from the roots of Dioscorea plants, has been shown to be effective in the management of metabolic disorders, regulation of inflammation, and inhibition of tumor growth. This study investigates the inhibitory effects of Dioscin on the proliferation and functionality of human scar fibroblasts (HSFs) and its therapeutic potential for HS, as well as the underlying mechanisms involved. The impact of Dioscin on collagen secretion and HSFs activation was assessed using Reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). HSFs functionality was evaluated through EdU proliferation, wound healing, transwell migration, and contracture assays. RNA sequencing revealed that Dioscin triggers HSFs apoptosis and ferroptosis by compromising mitochondrial membrane potential. Immunofluorescence and WB were employed to examine the mechanisms of Dioscin-induced apoptosis and ferroptosis. The therapeutic efficacy of Dioscin was further assessed in vivo using a rabbit ear scar model. Results show that Dioscin suppresses HSFs proliferation, migration, and contraction, reduces collagen secretion, and deactivates HSFs by destabilizing mitochondrial membrane potential, leading to ROS accumulation. Local administration of Dioscin significantly mitigates scar formation in rabbit ears. In conclusion, Dioscin reduces HS progression by disrupting mitochondrial membrane potential, inducing oxidative stress, and promoting apoptosis and ferroptosis in HSFs, highlighting its potential as a therapeutic agent for HS.