1β-hydroxyl-5α-chloro-8-epi-xanthatin Suppresses Inflammatory Responses by Targeting IKKα/β and Inhibiting the NF-κB Signaling Pathway.

Dysregulation of the nuclear factor-κB (NF-κB) cascade is tightly linked to the progression of inflammatory disorders. IκB kinases (IKKs) are well-established as central modulators of NF-κB activity, making them attractive therapeutic candidates for treating inflammatory pathologies. The sesquiterpene lactone 1β-hydroxyl-5α-chloro-8-epi-xanthatin (XTT) has been documented to exert robust anticancer effects. However, its anti-inflammatory activity and underlying molecular mechanisms remain unclear. In this work, XTT markedly suppressed the synthesis of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated RAW264.7 macrophages. XTT also substantially lowered LPS-triggered mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Furthermore, XTT downregulated the protein levels of iNOS and COX2 elicited by LPS treatment. At the mechanistic level, XTT did not notably alter the activity of the mitogen-activated protein kinase (MAPK) cascade. Conversely, XTT strongly blocked LPS-triggered phosphorylation and breakdown of inhibitory κBα (IκBα) by interacting with IKKα/β, thus impairing NF-κB nuclear translocation. Taken together, these data show that XTT elicits robust anti-inflammatory effects in vitro via targeting IKKα/β and blocking NF-κB signaling. These results suggest that XTT may serve as a promising lead compound for the development of anti-inflammatory agents. Further biochemical and in vivo studies are required to validate direct IKKα/β inhibition and therapeutic potential.