Dehydrocavidine alleviates lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway to inhibit hepatocyte ferroptosis

  • Phytomedicine. 2026 Jan 17:153:157845. doi: 10.1016/j.phymed.2026.157845.
Hongbiao Liang  1 ,  Guizimeng Hu  2 ,  Dongmin Yang  1 ,  Yuwei Song  1 ,  Peng Zhang  1 ,  Tianqi Chen  2 ,  Xiangrui Zhu  1 ,  Peiyi Li  2 ,  Yuan Wang  3 ,  Xinmei Huo  2 ,  Xiaoyi Wang  2 ,  Yi Zhang  2 ,  Yujie Zhang  2 ,  Jian Liu  2 ,  Juan Feng  4
Affiliations
  • 1. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 2. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 4. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China. Electronic address: [email protected].
PMID: 41653616 DOI: 10.1016/j.phymed.2026.157845
Abstract

Background: Sepsis-induced acute liver injury (SALI) remains a major challenge with limited effective treatments. Although Corydalis saxicola Bunting (CSB) exhibits anti-inflammatory and hepatoprotective properties, its role in SALI remains poorly understood.

Purpose: To identify the active components and molecular mechanisms of CSB in protecting against SALI.

Methods: In vivo LPS-induced rat liver injury and in vitro cytokine-induced HepG2 injury models were established, treated with CSB extract or dehydrocavidine (DC). A series of advanced techniques including Ferroptosis PCR array, super-resolution stimulated emission depletion (STED) microscopy, assay for transposase-accessible chromatin with Sequencing (ATAC-seq), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), molecular dynamics simulation, and site-directed mutation were employed to investigate the underlying mechanisms.

Results: DC significantly mitigated LPS-induced liver injury, microcirculatory disorder, and leukocyte adhesion. It also alleviated liver Ferroptosis under LPS challenge. In vitro studies revealed that LPS-activated macrophages secreted tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which triggered hepatocyte Ferroptosis. DC countered this process by inhibiting the production of these cytokines and correcting cytokine-induced mitochondrial abnormalities in hepatocytes. Mechanistically, DC bound to Kelch-like ECH-associated protein 1 (Keap1) at arginine 415 (R415), disrupting the formation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) complex. This enabled Nrf2 nuclear translocation and promoted antioxidant gene expression, thereby correcting LPS-induced redox imbalance in hepatocytes.

Conclusions: In addition to inhibiting LPS-induced macrophage activation, DC activates the Nrf2 signaling pathway in hepatocytes to alleviate inflammation-enhanced liver Ferroptosis. It provides potential therapeutic strategies for sepsis and Gram-negative bacteria-associated liver injury.

Keywords
Dehydrocavidine; Ferroptosis; LPS; Liver injury; Macrophage.
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