Cordycepin Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice by Inhibiting IL-6/IL-6R-Mediated p38 MAPK and NF-κB Activation Through Adenosine A<sub>2A</sub> Receptor Stimulation.

Abstract

<h4>Background</h4>Current ulcerative colitis (UC) therapies often cause adverse effects, and novel treatments are urgently needed. Cordycepin (COR), a bioactive compound from <i>Cordyceps militaris</i>, shows anti-inflammatory and intestinal protective potential, its precise role and mechanisms in UC remain unclear.<h4>Purpose</h4>This study aimed to elucidate the effects and underlying mechanisms of COR on UC.<h4>Methods</h4>Using dextran sulfate sodium (DSS)-induced acute colitis mice and DSS-damaged human colonic epithelial cells as models, we evaluated and analyzed the effects and mechanisms of COR on UC by combining molecular docking, molecular dynamics simulations, in vivo/in vitro interventions with selective pharmacological antagonists, transcriptome sequencing and Western blotting verification.<h4>Results</h4>In vitro experiments confirmed that COR exhibits protective effects on DSS-damaged colonic epithelial cells. Mechanistic studies revealed that COR elevates intracellular cAMP levels, and the selective adenosine A_2A receptor (A_2AAR) antagonist SCH58261 can block the protective effect of COR. Molecular docking and dynamics simulation analyses also demonstrated an interaction between COR and A_2AAR at the molecular level. In vivo experiments further verified that oral administration of COR (5 mg/kg, 10 mg/kg) significantly ameliorated DSS-induced colitis in mice, manifested by reduced disease activity index, attenuated weight loss, improved colon shortening, decreased serum pro-inflammatory cytokines, alleviated colonic inflammation, and restored intestinal barrier function. Moreover, the therapeutic effect of COR on colitis could be blocked by SCH58261. Further investigations indicated that COR inhibits IL-6/IL-6R signaling in colonic tissues and suppresses phosphorylation-mediated activation of p38 MAPK and NF-κB p65 through A_2AAR activation.<h4>Conclusion</h4>COR ameliorates DSS-induced colitis by activating A_2AAR to upregulate cAMP levels, inhibiting IL-6/IL-6R-mediated p38 MAPK and NF-κB activation. This study confirms A_2AAR as a key therapeutic target, providing data support for the potential application of COR in UC treatment.