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Inflammation occurs throughout the entire process of atherosclerosis. So, reducing the inflammatory response remains one of the main therapeutic strategies for atherosclerosis. Chensinin-1b, a derivative of the natural antimicrobial peptide extracted from the skin secretions of the Rana chensinensis, has been shown to effectively mitigate the occurrence of inflammatory responses. Here, the anti-inflammatory activity of the peptide by suppressing the canonical Wnt/β-catenin signaling pathway was investigated in ox-LDL-induced AS. The results showed that the classical Wnt/β-catenin signaling pathway was activated in ox-LDL-induced THP-1-derived foam cells. The inhibitor of Wnt reduced the release of pro-inflammatory cytokines by downregulating the NF-κB signaling pathway. Cyclooxygenase-2, a target protein of the canonical Wnt/β-catenin signaling pathway, inhibited the phosphorylation of NF-κB. Chensinin-1b and its analogs effectively downregulated the expression of Wnt signaling proteins by inhibiting the nuclear translocation of the key pathway protein β-catenin, resulting in a decrease in COX-2 expression and simultaneously reducing the release of pro-inflammatory cytokines. In summary, our study suggests the potential of chensinin-1b and its analogs as therapeutic agents for AS.