@article{APS11466,
author = {Yao Chen and Wen-qing Shi and Pei Zhang and Ran Wang and Wen-bo Ye and Guo-qiang Lin and Shou-jiao Peng and Jian-ge Zhang},
title = {Resibufogenin ameliorates cerebral ischemia-reperfusion injury by modulating microglial redox homeostasis via Keap1-Nrf2-TFR1/ARE axis},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {3},
year = {2026},
keywords = {},
abstract = {Cerebral ischemia-reperfusion injury (CIRI) represents a significant clinical challenge, with microglial homeostasis playing a critical role in its pathological progression. Venenum bufonis (VB) has been extensively utilized as a cardiotonic, analgesic, and antineoplastic agent in the clinical practice of traditional Chinese medicine. Resibufogenin (RBG) is a bufadienolide compound derived from VB that has a wide range of pharmacological activities, including antitumor, anti-inflammatory, and cardiovascular protective effects. In this study, we investigated the neuroprotective effects of RBG on the progression of CIRI and the underlying mechanisms. A CIRI model was established in rats by transient middle cerebral artery occlusion (tMCAO), after which the rats were administered RBG (2.6 or 4.0 mg·kg−1·d−1, i.g.) for 5 days. We showed that RBG administration markedly reduced cerebral infarct volume, restored neurological deficits, and mitigated neuronal loss in tMCAO rats. Quantitative proteomic analysis and robust experimental data revealed that RBG modulated microglial iron homeostasis by altering the binding affinity of the transcription factor Nrf2 to the antioxidant response element (ARE) within the promoter region of transferrin receptor protein 1 (TFR1). In BV2 cells under oxygen-glucose deprivation/reperfusion (OGD/R) conditions, RBG (5, 10, and 20 μM) dose-dependently modulated iron metabolism by increasing the expression of Nrf2 and the downstream antioxidants HO-1, NQO1, GCLC, and GCLM, thus restoring redox homeostasis. We found that RBG activated the Nrf2 signaling pathway by covalently binding to the Cys297 residue of Keap1, which was confirmed by site-directed mutagenesis in BV2 cells. In a BV2-PC12 cell coculture system subjected to OGD/R, RBG (20 μM) effectively alleviated neuronal apoptosis, whereas Nrf2 knockdown in BV2 cells abrogated the neuroprotective effect of RBG. Similarly, inhibition of Nrf2 using ML385 markedly diminished RBG-induced improvements in neurological behavior in tMCAO rats. Our results identify RBG as a new modulator of the Keap1-Nrf2-TFR1/ARE axis and suggest that RBG has promising neuroprotective potential against CIRI through its effects on microglial homeostasis.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11466}
}