Quercetin Ameliorates Skeletal Muscle Fibrosis After Injury by Interfering with Macrophage-Myofibroblast Transition.

Background: C3a-driven macrophage-myofibroblast transition (MMT) is a key pro-fibrotic event after acute skeletal muscle injury, with no effective treatment available. Quercetin is a bioactive flavonoid with anti-inflammation potential; however, its impact on muscle fibrosis remains unclear. Methods: scRNA-sequencing data of injured mouse skeletal muscle were analyzed with a focus on MMT, aiming to identify gene modules correlated with C3a. Network pharmacology was used to explore key biological processes involved in the potential anti-MMT effect of quercetin. We evaluated the therapeutic potential of quercetin using both BMDMs and a muscle contusion model to examine fibrosis amelioration and functional recovery. Results: scRNA-seq identified several signaling pathways and genes potentially implicated in quercetin-mediated inhibition of MMT. Network pharmacology highlighted four candidates (Ctsd, Stat1, Il1b, Cxcl10) as the targets of quercetin, which were proved by molecular docking results. In vitro, quercetin suppresses C3a-induced α-SMA upregulation in BMDMs. In vivo, histological findings showed quercetin reduced MMT at day 7, downregulated collagen deposition at day 14, and promoted the gait recovery of mice at day 28. Conclusion: Quercetin exhibits potential in mitigating muscle fibrosis following contusion and this effect may be mediated through its inhibition of MMT process.