Drug synergy is a promising new anti-aging strategy.Construction of the aging model induced by D-galactose in HUVEC cells was aimed to explore the potential synergistic anti-aging effect of acetylsalicylic acid and acetylcysteine,and to investigate the un-derlying mechanisms of their synergy in anti-aging.Network pharmacology was used to screen a group of small molecules with poten-tial anti-aging activity.D-galactose-induced HUVEC cells was employed to detect the anti-aging activity of small molecules,and Chou-Talalay model was used to screen two small molecule combinations with synergistic anti-aging effects.Further investigation of the mechanisms underlying the anti-aging activity mediated by the selected small molecule combinations was conducted using biochemical and cell biological approaches.Results showed that acetaminophen acid and acetylcysteine were a highly effective pair of small mole-cules with anti-aging activity,which could produce synergistic effects in mediating anti-aging.The synergistic combination significantly reduced intracellular reactive oxygen species levels,effectively relieved cell cycle arrest induced by D-galactose,and significantly re-duced the transcription levels of early inflammatory factors(IL-1β,COX-2).In addition,the synergistic combination significantly re-duced the protein levels of cell senescence markers(p53,p16),as well as p-p38 and nuclear p65 protein levels,indicating that the ace-tylsalicylic acid and N-acetylcysteine synergistic combination may inhibit cell aging via the MAPK/NF-κB pathway.These results provide a theoretical basis for the further development and utilization of acetylsalicylic acid and N-acetylcysteine as a synergistic anti-aging com-bination.
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