1&#946;-hydroxyl-5&#945;-chloro-8-epi-xanthatin Suppresses Inflammatory Responses by Targeting IKK&#945;/&#946; and Inhibiting the NF-&#954;B Signaling Pathway

Hai Zhang; Xiaofang Liu; Guangyu Song; Lun Wang; Xiaofei Shen

doi:10.3791/71253

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Research Article

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

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DOI:

10.3791/71253

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July 14th, 2026

Hai Zhang¹ , Xiaofang Liu¹ , Guangyu Song¹ , Lun Wang² , Xiaofei Shen³

¹College of Pharmacy, Chinese Medicine Germplasm Resources Innovation and Effective Uses Key Laboratory of Sichuan Province, Chengdu University of Traditional Chinese Medicine, ²Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, ³Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine

Summary

Sesquiterpene lactone XTT effectively attenuates lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. XTT targets IKKα/β to inhibit NF-κB signaling without affecting MAPK activation, thereby exerting potent anti-inflammatory effects in vitro.

Abstract

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.

Introduction

Inflammation is a tightly regulated biological process that enables organisms to respond to infection, tissue injury, and other environmental challenges¹. Although acute inflammatory responses are generally protective, persistent activation of inflammatory pathways can disrupt tissue homeostasis and contribute to the onset and progression of chronic disorders, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA)². Numerous intracellular signaling networks participate in inflammatory regulation, among which the nuclear factor-κB (NF-κB) pathway is one of the most extensively studied³