Beyond anti-inflammatory strategies: Epigenetic targets as emerging therapeutic frontiers in acute pancreatitis

Abstract

Acute pancreatitis (AP) remains a challenging clinical condition with limited therapeutic options and high mortality rates in severe cases. Traditional anti-inflammatory approaches have shown disappointing results in clinical trials, highlighting the urgent need for novel therapeutic strategies targeting the underlying pathophysiological mechanisms. The study by Jia et al presents compelling evidence for a previously unrecognized mechanism through which rutaecarpine, a bioactive alkaloid from traditional Chinese medicine, exerts protective effects against AP. This research demonstrates that rutaecarpine alleviates AP by targeting the epigenetic machinery, specifically through enhancer of EZH2-mediated suppression of FBXW11. The authors employed both in vitro cerulein-induced AR42J cell models and in vivo sodium taurocholate-induced rat models to establish the therapeutic efficacy of rutaecarpine and elucidate its molecular mechanisms. Their findings reveal that rutaecarpine upregulates EZH2 expression, leading to increased histone H3 methylation at the FBXW11 promoter region, thereby suppressing FBXW11 expression and consequently reducing inflammatory infiltration and oxidative stress. The significance of this work extends beyond demonstrating rutaecarpine’s protective effects. It identifies FBXW11 as a novel therapeutic target in AP and provides the first evidence that traditional Chinese medicine compounds can modulate epigenetic reprogramming in pancreatic inflammation. Recent studies have confirmed FBXW11’s role as an inflammatory biomarker in pancreatitis, supporting the clinical relevance of this pathway. The study’s comprehensive approach, combining molecular docking, cellular thermal shift assays, and co-immunoprecipitation studies, strengthens the mechanistic insights. These findings open new avenues for AP treatment by targeting epigenetic regulators rather than relying solely on conventional anti-inflammatory strategies, potentially leading to more effective therapeutic interventions for this devastating condition.

Keywords: Acute pancreatitis; Epigenetic regulation; Rutaecarpine; FBXW11; EZH2

Core Tip: Acute pancreatitis (AP) remains without effective mechanism-based therapy beyond supportive care. This editorial emphasizes epigenetic regulation as an emerging therapeutic frontier, highlighting how the traditional Chinese medicine alkaloid rutaecarpine protects against AP via enhancer of EZH2-mediated repression of FBXW11. By integrating evidence on FBXW11 as an inflammatory biomarker, the pleiotropic actions of rutaecarpine, and the clinical availability of EZH2 inhibitors, this article outlines an epigenetic, multi-target framework for future AP interventions.