2. Academic Validation
  3. Neferine Ameliorates Severe Acute Pancreatitis-Associated Intestinal Injury by Promoting NRF2-mediated Ferroptosis

Neferine Ameliorates Severe Acute Pancreatitis-Associated Intestinal Injury by Promoting NRF2-mediated Ferroptosis

  • Int J Biol Sci. 2025 Apr 28;21(7):3247-3261. doi: 10.7150/ijbs.112888.
Lilong Zhang 1 2 3 4,  Kunpeng Wang 1 2 3 4,  Wanrong Jiang 1 2 3 4,  Pingan Ding 5,  Weixing Wang 1 2 3 4,  Kailiang Zhao 1 2 3 4,  Chen Chen 1 2 3 4
Affiliations

Affiliations

  • 1 Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 2 Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 3 General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 4 Central laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 5 The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.
PMID: 40384872 DOI: 10.7150/ijbs.112888
Abstract

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.

Keywords

Acute pancreatitis; Ferroptosis; Gut microbiota; Intestinal injury; Iron export; Neferine.

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