Diminazene attenuates astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in Alzheimer's Disease Model

  • Neuropharmacology. 2026 May 15:289:110880. doi: 10.1016/j.neuropharm.2026.110880.
Zhaohan Xu  1 ,  Xiaoyuan Li  2 ,  Shiyao Wang  1 ,  Jinfeng Lyu  1 ,  Siqi Zhu  3 ,  Shuaiyu Chen  1 ,  Yihan Li  1 ,  Yingdong Zhang  4 ,  Feng Wang  5 ,  Rui Duan  6
Affiliations
  • 1. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.
  • 2. Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.
  • 3. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
  • 4. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China. Electronic address: [email protected].
  • 5. Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China. Electronic address: [email protected].
  • 6. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China; Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China. Electronic address: [email protected].
PMID: 41698644 DOI: 10.1016/j.neuropharm.2026.110880
Abstract

Purpose: Diminazene (DIZE), an agonist of the Ang-(1-7) system, has been proven to suppress astrocytic neuroinflammatory responses in Alzheimer's disease (AD). NADPH Oxidase 4 (NOX4) is abundantly expressed in astrocytes and critically mediates oxidative stress damage and Ferroptosis. However, the mode of DIZE in AD-related NOX4 overactivation and Ferroptosis remains to be revealed.

Methods: Male APP/PS1 mice received DIZE and the Ferroptosis inhibitor Liproxstatin-1 (LIP) treatment. Behavioral tests, Nissl staining, Western blotting, ELISA and immunofluorescence were performed to evaluate the effects of DIZE on neuronal loss, synaptic damage, inflammation and iron accumulation. Astrocytes from APP/PS1 mice were underwent high-throughput miRNA Sequencing to identity the most differentially expressed miRNAs after DIZE administration. Subsequently, the role of this miRNA in DIZE's anti-ferroptosis impact within primary astrocytes was explored.

Results: DIZE markedly reduced iron accumulation while lowering oxidative stress and inflammation in APP/PS1 mice. Simultaneously, DIZE significantly mitigated cognitive deficits and synaptic injury in APP/PS1 mice. DIZE suppressed the expression level of NOX4 and upregulated miR-10b-3p. Importantly, miR-10b-3p levels were notably elevated in astrocytes of APP/PS1 mice administered DIZE, targeting the NOX4 protein. Inhibition of miR-10b-3p expression significantly reversed the therapeutic effect of DIZE.

Conclusion: These findings indicate that DIZE suppresses astrocytic oxidative stress and neuronal Ferroptosis via miR-10b-3p/NOX4 axis in AD model.

Keywords
Alzheimer's disease; DIZE; Ferroptosis; NADPH oxidase 4; Oxidative stress; microRNAs.
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