Asthma　is　a　chronic　inflammatory　disorder　of　airway　affecting　people　from　childhood　to　old　age,　and　is　characterized　by　airway　epithelial　dysfunction.　Cucurbitacin　E　(CuE),　a　tetracyclic　triterpene　isolated　from　Cucurbitaceae　plants,　has　been　recently　proved　to　exert　anti-inflammation　and　immunology　regulation　activities.　Nevertheless,　its　roles　in　asthma　remains　poorly　defined.　In　the　current　study,　CuE　had　little　cytotoxicity　on　cell　viability　of　human　bronchial　epithelial　cell　line　BEAS-2B.　Moreover,　lipopolysaccharide　(LPS)　exposure　inhibited　cell　viability　and　induced　cell　apoptosis,　which　was　reversed　following　CuE　pretreatment.　Additionally,　CuE　administration　suppressed　LPS-induced　inflammatory　cytokine　production,　including　TNF-alpha,　IL-6,　and　IL-8.　Simultaneously,　supplementation　with　CuE　decreased　the　transcripts　and　releases　of　mucin　5AC　(MUC5AC)　in　LPS-treated　BEAS-2B　cells.　Intriguingly,　CuE　inhibited　LPS-evoked　activation　of　the　high-mobility　group　box1　(HMGB1)-TLR4-NF-kappa　B　signaling　by　reducing　the　expression　of　HMGB1,　TLR4　and　p-p65　NF-kappa　B.　Notably,　restoring　this　pathway　by　elevating　HMGB1　expression　largely　offset　the　protective　function　of　CuE　against　LPS-triggered　cell　injury,　inflammatory　response　and　MUC5AC　expression.　Consequently,　these　findings　highlight　that　CuE　can　ameliorate　human　bronchial　epithelial　cell　insult　and　inflammation　under　LPS-simulated　asthmatic　conditions　by　blocking　the　HMGB1-TLR4-NF-kappa　B　signaling,　thereby　supporting　its　usefulness　as　a　promising　therapeutic　agent　against　asthma.