Indomethacin alleviates acute pancreatitis by restoring autophagic flux via the AMPK signaling pathway.

Abstract

Acute pancreatitis (AP) remains a significant clinical challenge lacking early, targeted pharmacological interventions to prevent disease progression. Dysfunctional autophagy is a central pathogenic mechanism in AP. While indomethacin (IND), a nonsteroidal anti-inflammatory drug, is known to prevent post-ERCP pancreatitis, its broader therapeutic potential and underlying mechanisms in other forms of AP are unclear. Emerging evidence suggests that IND has the potential to activate autophagy. This study aimed to investigate whether IND protects against AP by regulating autophagy. We established cerulein (CER)-induced AP models both in vivo and in AR42J cells to evaluate the protective effects of IND. Transcriptomic and pathway analyses were conducted to identify underlying signaling mechanisms. Our results demonstrate that IND alleviated CER-induced pancreatic injury, as indicated by improved histopathological scores, reduced serum amylase and lipase levels, diminished inflammatory cell infiltration, and attenuated acinar cell cytotoxicity. Mechanistically, transcriptomic and experimental data revealed that IND restored autophagy via activation of the AMP-activated protein kinase (AMPK) signaling pathway. Critically, the protective effects of IND were abolished by either the autophagy inhibitor chloroquine or the AMPK inhibitor Compound C (CC). In conclusion, our findings suggest that IND may serve as a promising therapeutic candidate for the treatment of AP.