Glabridin Suppresses LPS-Induced Inflammatory Cascade by Targeting AMPK/JAK2/STAT3 Pathways in Macrophages

Objectives: Inflammation, a crucial biological response defending the body against harmful stimuli, has been a central focus in medicinal research. Licorice root, rich in bioactive compounds, contains glabridin (GBD), a renowned natural flavonoid with anti-inflammatory and antioxidant properties. Despite its recognition, the precise molecular mechanisms underlying GBD's anti-inflammatory effects remain a subject of ongoing investigation. Methods: This study explores the impact of GBD on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages, aiming to unravel intricate molecular pathways, specifically focusing on the potential involvement of the adenosine monophosphate-activated protein kinase (AMPK)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. The study first determined the effective dose of GBD by measuring its impact on the production of pro-inflammatory mediators in response to LPS stimulation. The novelty of this study lies in subsequent examination of GBD's effects under LPS-induced inflammation, an aspect that has not been thoroughly explored in previous research. Results: GBD inhibits the production of LPS-induced pro-inflammatory cytokines and nitric oxide (NO). It also suppresses the expression of iNOS and IL-1β induced by LPS. Furthermore, GBD attenuates LPS-induced phosphorylation of JAK2 and STAT3, concurrently inhibiting AMPK phosphorylation. The study further elucidates the relationship between AMPK and JAK2/STAT3 using JAK2 inhibitor, AG490, and AMPK inhibitor, compound C (CC). Importantly, CC not only inhibits the expression of AMPK but also suppresses the expression of JAK2 and STAT3. This observation strongly suggests that GBD modulates the AMPK/JAK2/STAT3 signaling pathways in LPS-stimulated macrophages. Conclusion: This study reveals that GBD is a promising anti-inflammatory agent with novel inhibitory effects on the AMPK/JAK2/STAT3 pathway, highlighting its potential therapeutic value for inflammatory diseases.