C498-0670 ameliorates severe acute pancreatitis through dual modulation of NF-κB and STAT3 signaling pathways.

Abstract

Severe acute pancreatitis (SAP) is a critical inflammatory condition characterized by extensive pancreatic injury and systemic inflammatory complications. Despite its high morbidity and mortality, current clinical management remains largely supportive, and no targeted anti-inflammatory therapies have proven effective. This study aimed to evaluate the therapeutic potential and mechanistic basis of C498, a novel small-molecule compound, in a murine model of SAP induced by caerulein and lipopolysaccharide (LPS). C498 was administered at varying doses under both prophylactic and therapeutic regimens. Pancreatic damage was assessed via histopathological examination and serum enzyme measurements. Inflammatory responses were quantified by RT-qPCR and ELISA. Transcriptomic profiling and Western blotting were performed to identify differentially expressed genes and involved signaling pathways. C498 administration significantly attenuated pancreatic injury, as evidenced by reduced tissue edema, necrosis, and inflammatory infiltration, along with markedly decreased serum amylase and lipase levels. Inflammatory cytokines including TNF-α, IL-6, and IL-1β were significantly downregulated in C498-treated mice. Transcriptomic and immunoblot analyses revealed that C498 effectively suppressed key pro-inflammatory signaling cascades, particularly NF-κB and STAT3, as shown by reduced phosphorylation levels of NF-κB p65 and STAT3. Additionally, no signs of systemic toxicity or histopathological abnormalities were observed in major organs.C498 exhibits potent anti-inflammatory effects in SAP by modulating NF-κB and STAT3 signaling pathways. These findings support the potential of C498 as a promising therapeutic candidate for the treatment of SAP.