Targeted Metabolomics Uncovers NorCA's Role as a Potent Immunomodulator in Acute Pancreatitis by Promoting Macrophage Reprogramming and Efferocytosis.

Acute pancreatitis (AP) is a severe inflammatory disorder with limited therapeutic options. Novel bile acids have emerged as potent immunomodulators, but the function of norcholic acid (NorCA) previously remained unknown. In this study, we identified NorCA's role as a novel immunomodulator that alleviates acute pancreatitis through peroxisome proliferator-activated receptor α (PPARα)-mediated macrophage reprogramming and efferocytosis. Targeted metabolomics was performed on serum from patients with AP and caerulein-induced AP mice. The functional role and mechanism of NorCA were investigated using flow cytometry, immunofluorescence, efferocytosis assays, and network pharmacology, both in vitro and in vivo. Our findings indicate that NorCA levels were significantly elevated in both patients and mice with AP, correlating with disease severity and complications. NorCA treatment markedly reduced serum amylase/lipase and pancreatic histopathological damage in AP mice. Mechanistically, NorCA promoted M1-to-M2 macrophage reprogramming and enhanced efferocytosis of apoptotic cells. These effects were dependent on PPARα activation, as demonstrated by siRNA silencing and pharmacological antagonism. These findings position NorCA as a promising therapeutic candidate and severity-associated metabolite in AP.