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 A2A Receptor Stimulation

Background: Current ulcerative colitis (UC) therapies often cause adverse effects, and novel treatments are urgently needed. Cordycepin (COR), a bioactive compound from Cordyceps militaris, shows anti-inflammatory and intestinal protective potential, its precise role and mechanisms in UC remain unclear.

Purpose: This study aimed to elucidate the effects and underlying mechanisms of COR on UC.

Methods: 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.

Results: 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.

Conclusion: 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.

adenosine receptor A2A; colonic inflammation; cordycepin; intestinal barrier function; ulcerative colitis.