What question did this study set out to answer?

The research aims to investigate the effects of cordycepin on ulcerative colitis and its mechanisms of action.

March 26, 2026Open Access

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

Key Points

The research aims to investigate the effects of cordycepin on ulcerative colitis and its mechanisms of action.
Utilized DSS-induced acute colitis mice and DSS-damaged human colonic epithelial cells to model UC.
Conducted molecular docking and dynamics simulations to analyze interactions.
Used selective pharmacological antagonists and transcriptome sequencing to examine mechanisms.
Performed Western blotting for verification of protein activation and inhibition.
Cordycepin protected DSS-damaged colonic epithelial cells in vitro.
Oral administration of cordycepin significantly improved colitis symptoms in mice, reducing disease activity and weight loss.
Increased levels of intracellular cAMP were observed with cordycepin treatment.
The protective effects of cordycepin were blocked by the A2A receptor antagonist SCH58261.
Cordycepin inhibited IL-6 signaling and the activation of p38 MAPK and NF-kB pathways.

Abstract

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 2A AR) antagonist SCH58261 can block the protective effect of COR. Molecular docking and dynamics simulation analyses also demonstrated an interaction between COR and A 2A AR 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 2A AR activation. Conclusion: COR ameliorates DSS-induced colitis by activating A 2A AR to upregulate cAMP levels, inhibiting IL-6/IL-6R-mediated p38 MAPK and NF-κB activation. This study confirms A 2A AR as a key therapeutic target, providing data support for the potential application of COR in UC treatment. Keywords: ulcerative colitis, adenosine receptor A 2A , cordycepin, colonic inflammation, intestinal barrier function

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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

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