Piperlongumine alleviates colitis by promoting β-catenin proteasomal degradation to inhibit NLRP3 inflammasome activation and pyroptosis.

Ulcerative colitis is a chronic inflammatory disorder characterized by diffuse mucosal inflammation confined to the colon and rectum. Long pepper is a widely used condiment for stews and barbecues and is known for its potential nutritional and medicinal value. Piperlongumine (PPL), the major active component of long pepper, represents a promising anti-inflammatory agent. However, the precise mechanism by which PPL regulates colitis remains unclear and requires further elucidation. In this study, we found that PPL interfered with NLRP3 inflammasome assembly in mouse and human macrophages and inhibited inflammasome-mediated pyroptosis. Mechanistic exploration revealed that PPL impaired NLRP3-ASC complex assembly and subsequent inflammasome activation largely by promoting β-catenin proteasomal degradation and reducing β-catenin abundance, with a minor contribution from a β-catenin-independent pathway. Most importantly, PPL alleviated pathological features of dextran sulfate sodium-induced colitis, including colorectal shortening, body weight loss, occult blood, and decreased neutrophil infiltration. In summary, PPL is a food-derived ingredient with anti-inflammatory properties that ameliorates colitis by suppressing NLRP3 inflammasome activation and pyroptosis.