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Acute pancreatitis (AP) is a non-infectious pancreatic enzyme-induced disorder, a life-threatening inflammatory condition that can cause multi-organ dysfunction, characterized by high morbidity and mortality. Several therapies have been employed to target this disorder; however, few happen to be effectively employable even in the early phase. PFKFB3(6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) is a critical regulator of glycolysis and is upregulated under inflammatory, mitogenic, and hypoxia conditions. Essential information on the targeting of the inflammatory pathway will present the termination of the disorder and recovery. Herein we investigated the protective function of KAN0438757, a potent inhibitor of PFKFB3, and its mechanism of impeding AP induced in mice. KAN0438757 was confirmed to activate the Nrf2/HO-1 inflammatory signaling pathways in response to caerulein induced acute pancreatitis (CAE-AP) and fatty acid ethyl ester induced severe acute pancreatitis (FAEE-SAP). Additionally, KAN0438757 alleviated the inflammatory process in infiltrated macrophage via the Nrf2/HO-1 inflammatory signaling pathway and demonstrated a significant effect on the growth of mice with induced AP. And more importantly, KAN0438757 displayed negligible toxicity in vivo. Taken together our data suggest KAN0438757 directly suppresses the inflammatory role of PFKFB3 and induces a protective role via the Nrf2/HO-1 pathway, which could prove as an excellent therapeutic platform for SAP amelioration. [Display omitted] • KAN0438757 alleviated the inflammatory process in infiltrated macrophages. • KAN0438757 demonstrates negligible toxicity in vivo. • KAN0438757 suppresses the inflammatory role of PFKFB3. • KAN0438757 induces a protective role via the Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

Summary: Acute pancreatitis (AP), an inflammatory disorder of the pancreas with a high hospitalization rate, frequently leads to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). However, therapeutic targets for effective treatment and early intervention of AP are still urgently required to be identified. Here, we have observed that the expression of pancreatic lincRNA‐EPS, a long intergenic non‐coding RNA, is dynamically changed during both caerulein‐induced AP (Cer‐AP) and sodium taurocholate‐induced severe AP (NaTc‐SAP). The expression pattern of lincRNA‐EPS is negatively correlated with the typical inflammatory genes such as IL‐6, IL‐1β, CXCL1, and CXCL2. Further studies indicate that knockout of lincRNA‐EPS aggravates the pathological symptoms of AP including more induction of serum amylase and lipase, severe edema, inflammatory cells infiltration and acinar necrosis in both experimental AP mouse models. Besides these intrapancreatic effects, lincRNA‐EPS also protects against tissue damages in the extra‐pancreatic organs such as lung, liver, and gut in the NaTc‐SAP mouse model. In addition, we have observed more serum pro‐inflammatory cytokines TNF‐α and IL‐6 in the lincRNA‐EPS‐/‐ NaTc‐SAP mice and more extracellular HMGB1 around injured acinar cells in the pancreas from lincRNA‐EPS‐/‐ NaTc‐SAP mice, compared with their respective controls. Pharmacological inhibition of NF‐κB activity by BAY11‐7082 significantly abolishes the suppressive effect of lincRNA‐EPS on TLR4 ligand‐induced inflammatory genes in macrophages. Our study has described a protective role of lincRNA‐EPS in alleviating AP and SAP, outlined a novel pathway that lincRNA‐EPS suppresses HMGB1‐NF‐κB‐dependent inflammatory response in pancreatic macrophages and provided a potential therapeutic target for SAP. [ABSTRACT FROM AUTHOR]