Bone fracture induces an acute inflammatory response in the resident and peripheral monocyte/macrophage cells. Excessive amounts of proinflammatory cytokines can cause severe tissue damage and inhibit bone healing. The proinflammatory cytokine genes are mainly controlled by TLR4/NF-κB (Toll-like receptor 4/Nuclear factor κB). Thus, targeting the molecules in this signaling pathway to decrease the expression of proinflammatory cytokines is an effective strategy to inhibit the inflammatory response. Herein, we identified a naturally derived small molecule NDSM253 that specifically inhibited IKKα (Inhibitor of NF-κB kinase subunit-alpha), a critical component of TLR4/NF-κB signaling. Biochemically, NDMS253 decreased phosphorylation of IκB (Inhibitor of NF-κB), thereby increasing the binding of IκB-NF-κB and suppressing the proinflammatory cytokine gene expression. NDMS253 showed a much stronger inhibitory effect on proinflammatory cytokine gene expression than did the known IKK inhibitors, including ACHP (2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile), IKK16, and Amlexanox. Administration of these IKK inhibitors in a mouse femoral fracture model showed that NDSM253 suppressed proinflammatory cytokine genes, thereby promoting bone healing, while the other three IKK inhibitors showed a weaker improvement of both bone healing and circulating proinflammatory cytokines. Collectively, our data suggested that NDSM253 might be an effective inhibitor of IKKα that could inhibit inflammatory cytokine action in bone injury. AJTR Copyright © 2021.