胰腺纤维化是慢性胰腺炎（CP）特征性病理改变，胰腺星状细胞（PSC）活化是CP纤维化关键事件。既往研究发现活性氧在PSC活化中扮演重要角色，NADPH氧化酶（NOX）是细胞内活性氧的重要来源，其中NOX4可参与心脏重塑及肝、肾纤维化。近期研究发现晚期糖基化终末产物（AGEs）可通过其受体（RAGE）调节NOX表达参与糖尿病并发症、肝纤维化等疾病。申请人前期研究发现CP患者血清AGEs增多；转录组测序提示小鼠活化PSC中NOX4表达升高，AGEs-RAGE通路富集；进一步用AGEs刺激原代PSC后细胞活化且NOX4表达增加。据此推测，AGEs与PSC表面RAGE受体结合后促进NOX4表达诱发氧化应激，导致PSC活化。本研究拟利用NOX4抑制剂、siRNA干扰技术以及NOX4基因敲除小鼠在体外及体内水平阐述AGEs促进胰腺纤维化的分子机制，探讨NOX4作为靶点治疗CP的潜在价值。

Pancreatic fibrosis is a characteristic pathological change in chronic pancreatitis (CP), and activation of pancreatic stellate cell (PSC) is a key event in CP fibrosis. Previous studies have found that reactive oxygen species play an important role in PSC activation. NADPH oxidase (NOX) is an important source of intracellular reactive oxygen species, while NOX4 is involved in cardiac remodeling and liver and kidney fibrosis. Recent studies have found that NOX expression could be regulated by advanced glycation end products (AGEs) through their receptors (RAGE) to participate in diseases such as diabetic complications and liver fibrosis. Our previous study found that serum AGEs were increased in CP patients. Transcriptome sequencing indicated that NOX4 expression was increased and AGEs-RAGE pathway was enriched in activated PSCs. After stimulated with AGEs, primary PSCs were activated and NOX4 increased. It is speculated that AGEs bind to the RAGE receptor on the surface of PSC and induce oxidative stress by promoting NOX4 expression, which activates PSCs. In this study, we intends to use NOX4 inhibitors, siRNA interference technology and NOX4 knockout mice to explicit the molecular mechanism of AGEs promoting pancreatic fibrosis in vitro and in vivo, and evaluating the potential value of NOX4 as a therapeutic target for of CP.