TIGAR Alleviates Acute Pancreatitis by Suppressing Glycolysis Through the LAMP2/PI3K/Akt Axis.

Abstract

Acute pancreatitis (AP) is a prevalent inflammatory disorder of the pancreas, with emerging evidence implicating aberrant acinar cell glycolysis in disease progression. Although TIGAR (TP53-induced glycolysis and apoptosis regulator), a key glycolytic regulator, has been implicated in various pathological processes, its role in AP remains unexplored. In this study, we established an AP mouse model through intraperitoneal injection of high-dose caerulein. AP mice exhibited downregulated pancreatic TIGAR expression accompanied by enhanced glycolysis. In vitro, primary pancreatic acinar cells were stimulated with LPS to mimic the inflammatory microenvironment. TIGAR overexpression effectively mitigated LPS-induced reductions in cell viability, inflammatory cytokine expression, reactive oxygen species (ROS) production, and glycolytic activation. Notably, LAMP2 (lysosome-associated membrane protein 2) knockdown abolished the protective effects of TIGAR against LPS-induced ROS, inflammation, and glycolytic flux. Mechanistically, TIGAR suppressed LPS-induced glycolytic activation by upregulating LAMP2 expression, thereby inhibiting PI3K/Akt pathway activation. Consistently, the glycolytic inhibitor 2-DG reversed the detrimental effects of TIGAR knockdown on cell viability and inflammatory responses. Furthermore, both preventive and therapeutic AAV8-TIGAR administration attenuated AP progression in mice. In conclusion, our findings demonstrate that TIGAR protects against AP progression by modulating the LAMP2/PI3K/Akt axis to maintain glycolytic homeostasis, highlighting its potential as a therapeutic target for AP.