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

Yu Liao,1 Weipeng Wei,1 Fuli Qin,1 Yusheng Ruan,1 Ting He,1 Jiansong He,1 Mingchao Wang,2 Taotao Liu,1 Jiemei Chen1 1Department of Pharmacy, the First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Taotao Liu; Jiemei Chen, Email [email protected]; [email protected]: 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 A2A receptor (A2AAR) antagonist SCH58261 can block the protective effect of COR. Molecular docking and dynamics simulation analyses also demonstrated an interaction between COR and A2AAR 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 A2AAR activation.Conclusion: COR ameliorates DSS-induced colitis by activating A2AAR to upregulate cAMP levels, inhibiting IL-6/IL-6R-mediated p38 MAPK and NF-κB activation. This study confirms A2AAR as a key therapeutic target, providing data support for the potential application of COR in UC treatment.Keywords: ulcerative colitis, adenosine receptor A2A, cordycepin, colonic inflammation, intestinal barrier function