Background: Sarcopenia is an age-related degenerative disease often accompanied by chronic low-grade inflammation and fibrotic remodeling, yet its specific underlying mechanisms remain unclear. This study aimed to explore the potential mechanism by which ginsenoside Rg2 ameliorates aging-related sarcopenia, with particular attention to TGF-(31/Smad-mediated fibrosis. Methods: Using single-cell sequencing, transcriptomic analysis, and Mendelian randomization (MR), we identified a causal relationship between transforming growth factor-(31 (TGF-(31)-mediated fibrosis and the progression of sarcopenia. We employed siRNA-mediated gene knockdown, real-time quantitative polymerase chain reaction (RT-qPCR), grip strength testing, western blotting, histological staining, molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays to evaluate the effects and potential mechanisms of Rg2 in aged male mice and C2C12 cell models. Results: Single-cell sequencing and MR analyses revealed that aging was associated with depletion of muscle satellite cells and skeletal muscle cells, together with increased neutrophils and fibroblasts. TGF-(31-related signaling showed a genetically supported association with sarcopenia-related traits and was closely associated with fibrotic remodeling in aged skeletal muscle. Rg2 treatment significantly mitigated age-associated weight gain while improving muscle mass, strength, and exercise endurance. Mechanistically, Rg2 interacted with TGF(31 and attenuated downstream Smad2/3 phosphorylation in vitro and in vivo, thereby modulating inflammatory and fibrosis-related markers and partially reversing muscle tissue and cellular senescence. Conclusion: Our findings suggest that ginsenoside Rg2 alleviates TGF-(31/Smad-mediated fibrotic remodeling and improves the aging-related inflammatory-fibrotic microenvironment during skeletal muscle aging.
