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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]