A Keap1-Nrf2 protein-protein interaction inhibitor 4-95 ameliorates cognitive dysfunction by suppressing neuronal ferroptosis

  • Bioorg Chem. 2026 Jun 17:180:110134. doi: 10.1016/j.bioorg.2026.110134.
Ruyun Liu  1 ,  Minzhen Wei  1 ,  Lijuan Xu  2 ,  Zhuo Qu  1 ,  Jian-Qiang Yu  1 ,  Yue Liu  1 ,  Wan-Nian Zhang  3 ,  Danfeng Zhang  4 ,  Chunlin Zhuang  5
Affiliations
  • 1. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
  • 2. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 3. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 4. Department of Neurosurgery, Second Affiliated Hospital of Naval Medical University, Shanghai Institute of Neurosurgery, Shanghai 200003, China. Electronic address: [email protected].
  • 5. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: [email protected].
PMID: 42322910 DOI: 10.1016/j.bioorg.2026.110134
Abstract

Alzheimer's disease (AD) is a severe neurodegenerative disorder. With current therapies failing to halt clinical progression, identifying novel disease-modifying therapeutics is of paramount urgency. Although Ferroptosis has emerged as a crucial driver of AD pathogenesis, effective pharmacological strategies targeting this pathway remain limited. Bioinformatic analysis revealed close associations among Ferroptosis, oxidative stress, the Keap1-Nrf2 pathway, and AD. Compound 4-95, a selective Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, significantly alleviated Erastin and RSL-3-induced Ferroptosis in SH-SY5Y and HT-22 cells. In Aβ1-42-treated cell models, 4-95 dose-dependently decreased Aβ and p-Tau expression, while increasing the anti-ferroptotic proteins GPX4 and SLC7A11. Keap1 and GPX4 knockdown verified that 4-95 inhibits Ferroptosis via the Keap1-Nrf2-GPX4 axis. In vivo, 4-95 markedly improved cognitive and spatial memory deficits in Aβ1-42-induced AD mice, promoted Nrf2 nuclear translocation, upregulated the downstream antioxidant targets HO-1 and NQO1, and attenuated neuronal injury. Collectively, the study reveals a new mechanism of a Keap1-Nrf2 PPI inhibitor that mitigates AD pathogenesis by directly inhibiting Ferroptosis. This novel mechanism underscores a new class of disease-modifying candidates for AD treatment, representing a new therapeutic strategy for this devastating disorder.

Keywords
Alzheimer's disease; Antioxidant; Ferroptosis; Keap1; Nrf2; Protein–protein interaction.
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