Zhang Lilong, Wang Kunpeng, Jiang Wanrong, Ding Pingan, Wang Weixing, Zhao Kailiang, Chen Chen
Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
Int J Biol Sci. 2025 Apr 28;21(7):3247-3261. doi: 10.7150/ijbs.112888. eCollection 2025.
Severe acute pancreatitis (SAP) is a life-threatening abdominal condition often complicated by intestinal barrier dysfunction, which further exacerbates disease progression. Neferine has demonstrated potent anti-inflammatory and antioxidant properties; however, its role in ameliorating SAP and associated intestinal barrier damage remains unclear. In this study, we found that neferine administration significantly alleviates SAP severity by reducing pancreatic and ileal pathological damage, oxidative stress, inflammatory cell infiltration, and intestinal flora translocation. Additionally, neferine enhances the expression of tight junction proteins, increases short-chain fatty acid levels, and improves intestinal dysbiosis, thereby contributing to intestinal homeostasis restoration. Mechanistically, neferine upregulates Nrf2 expression and promotes its nuclear translocation by competitively binding to the Cys-288 site on Keap1. This activation enhances the Nrf2/FPN and Nrf2/xCT/GPX4 axes, thereby preventing ferroptosis and ultimately protecting against pancreatic and intestinal injury in SAP mice. Furthermore, the protective effects of neferine were largely reversed by the Nrf2 inhibitor ML385 and the ferroptosis inducer erastin. This study demonstrates that neferine effectively alleviates SAP by inhibiting ferroptosis and restoring intestinal homeostasis, providing insights into new treatment options for SAP.
重症急性胰腺炎（SAP）是一种危及生命的腹部疾病，常伴有肠道屏障功能障碍，这会进一步加剧疾病进展。甲基莲心碱已显示出强大的抗炎和抗氧化特性；然而，其在改善SAP及相关肠道屏障损伤中的作用仍不清楚。在本研究中，我们发现给予甲基莲心碱可通过减轻胰腺和回肠的病理损伤、氧化应激、炎症细胞浸润及肠道菌群易位，显著减轻SAP的严重程度。此外，甲基莲心碱可增强紧密连接蛋白的表达，提高短链脂肪酸水平，并改善肠道菌群失调，从而有助于恢复肠道稳态。机制上，甲基莲心碱通过与Keap1上的Cys-288位点竞争性结合来上调Nrf2表达并促进其核转位。这种激活增强了Nrf2/FPN和Nrf2/xCT/GPX4轴，从而防止铁死亡，并最终保护SAP小鼠免受胰腺和肠道损伤。此外，Nrf2抑制剂ML385和铁死亡诱导剂erastin在很大程度上逆转了甲基莲心碱的保护作用。本研究表明，甲基莲心碱通过抑制铁死亡和恢复肠道稳态有效减轻SAP，为SAP的新治疗选择提供了见解。
