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Atherosclerosis (AS) is an inflammatory disease, whose occurrence and development mechanism is related to a great number of inflammatory cytokines. β -sitosterol (BS), a natural compound extracted from numerous vegetables and plant medicines, has been suggested to improve AS, but the underlying mechanism remains vague. This work focused on investigating how BS affected the lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs) and further exploring the potential targets and mechanisms through network pharmacology (NP) and molecular docking (MD). According to in vitro experiments, LPS resulted in an increase in the expression of inflammatory cytokines like tumor necrosis factor- α (TNF- α ), cyclooxygenase-2 (Cox-2), and interleukin-6 (IL-6). Besides, secretion of IL-6, interleukin-1 β (IL-1 β ), and TNF- α also increased in HUVECs, whereas BS decreased the expression and secretion of these cytokines. NP analysis revealed that the improvement effect of BS on AS was the result of its comprehensive actions targeting 99 targets and 42 pathways. In this network, MAPKs signaling pathway was the core pathway, whereas MAPK1, MAPK8, MAPK14, and NFKB1 were the hub targets. MD analysis also successfully validated the interactions between BS and these targets. Moreover, verification test results indicated that BS downregulated the abnormal expression and activation of MAPKs and NF- κ B signaling pathways in LPS-treated cells, including p38, JNK, ERK, NF- κ B, and I κ B- α phosphorylation expressions. Furthermore, p65 nuclear translocation was also regulated by BS treatment. In conclusion, the BS-related mechanisms in treating AS are possibly associated with inflammatory response inhibition by regulating MAPKs and NF- κ B signaling pathways., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Yiming Bi et al.)