Bilirubin prevents hyperlipidaemic acute pancreatitis by inhibiting aryl hydrocarbon receptor‐mediated acinar cell pyroptosis

Background and Purpose Hyperlipidaemia‐induced acute pancreatitis (HLAP) represents a specific subtype of acute pancreatitis (AP) characterised by elevated serum triglyceride levels. However, the precise pathophysiological mechanisms underlying HLAP remain unclear. Bilirubin, an essential haem metabolite, displays significant capabilities in neutralising oxidative stress and modulating inflammatory responses. Here, we investigate the role of bilirubin in mediating HLAP. Experimental Approach We analysed the serum from 627 AP patients, including 160 HLAP patients and 467 non‐HLAP patients. Using an experimental HLAP mouse model, knockout mice and an aryl hydrocarbon receptor (AHR) inhibitor, we evaluated the role and underlying mechanism of bilirubin during HLAP development. Key Results Bilirubin levels were significantly down‐regulated in HLAP patients, and this decrease is correlated positively with the severity of the disease. Additionally, in the HLAP mouse model, we found that bilirubin supplementation mitigates lipid dysregulation and reduces pancreatic inflammation. Moreover, the Nrf2/HO‐1 pathway is an upstream activator of bilirubin accumulation. Our data showed that Nrf2 −/− HLAP mice exhibited enhanced pancreatic injuries compared with control mice. Furthermore, transcriptome analysis demonstrated marked elevation of the NOD‐like receptor pathway in pancreatic tissue of HLAP mice, and bilirubin supplementation notably inhibited pancreatic pyroptosis. In addition, using an aryl hydrocarbon receptor (AHR) inhibitor and a pancreatic acinar cell line, we demonstrated that bilirubin prevents HLAP by inhibiting AHR‐mediated pyroptosis. Conclusions and Implications Our data demonstrated that bilirubin protects against HLAP by suppressing AHR‐mediated pyroptosis, highlighting bilirubin modulation as a potential therapeutic target for clinical intervention.