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This study aims to explore the screening and mechanisms of action of traditional Chinese medicine(TCM) monomer compounds targeting transient receptor potential vanilloid 4(TRPV4) against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). Based on a machine learning method using the pre-trained protein language model ConPLex to predict drug-target binding properties, the study rapidly screened TRPV4-targeting TCM monomer compounds and ranked them by algorithm scores from highest to lowest. The cytotoxicity of candidate compounds was evaluated via cell counting kit-8(CCK-8), and the effects of glycycoumarin(GCM) on SARS-CoV-2 replication in African green monkey kidney cell line(Vero-E6) were analyzed through indirect immunofluorescence assay(IFA) and Western blot. A BALB/c mouse infection model with SARS-CoV-2/C57MA14 mouse-adapted strain was employed to assess the in vivo antiviral efficacy of GCM by examining the survival rate, pulmonary viral load, and pathological damage. To elucidate the molecular mechanism, Western blot was used to detect the protein expression of key signaling pathways, and enzyme-linked immunosorbent assay(ELISA) was applied to quantify concentrations of cytokines including interleu-kin-6(IL-6), tumor necrosis factor-alpha(TNF-α), C-X-C motif chemokine ligand 10(CXCL10), and monocyte chemoattractant protein-1(MCP-1) in serum. Molecular docking and molecular dynamics simulation techniques were employed to resolve the binding mode of GCM with the TRPV4 protein. In vitro experiments demonstrated that among 15 candidate compounds, GCM exhibited significant dose-dependent inhibition of SARS-CoV-2. In the animal model, the compound prolonged the survival time of infected mice and significantly alleviated virus-induced pulmonary pathological damage. Mechanistic studies revealed that GCM suppressed the TRPV4 expression, blocked nuclear translocation of nuclear factor kappa-B(NF-κB) triggered by SARS-CoV-2 infection, and subsequently downregulated the transcriptional level of pro-inflammatory factors such as IL-6 and TNF-α. Concurrently, the expression of IL-6, TNF-α, CXCL10, and MCP-1 in serum was markedly reduced after GCM intervention. The molecular docking and dynamics simulation confirmed that the GCM-TRPV4 compound exhibited excellent stability in both binding conformation and dynamic interactions. The study verified that GCM demonstrated potent anti-SARS-CoV-2 activity in both in vitro and in vivo models, effectively inhibiting viral replication while suppressing infection-induced cytokine storms. The results indicate that GCM is a highly promising anti-SARS-CoV-2 TCM monomer compound, which is worthy of further in-depth research and development.