2. Academic Validation
  3. Phactr4 promotes oxidative stress and behavioral disorder caused by chronic stress via regulating PP1/GSK3-β pathway

Phactr4 promotes oxidative stress and behavioral disorder caused by chronic stress via regulating PP1/GSK3-β pathway

  • Redox Biol. 2025 Sep 16:87:103873. doi: 10.1016/j.redox.2025.103873.
Tian Lan 1,  Ye Li 1,  Wanzhe Zhang 1,  Xiao Chen 1,  Mengni Chang 1,  Wenjing Wang 1,  Changmin Wang 1,  Shihong Chen 2,  Linghua Kong 3,  Shuyan Yu 4
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, The Second Hospital of Shandong University, Jinan, Shandong Province, 250012, China; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, 250012, China.
  • 2 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, Shandong Province, 250033, China. Electronic address: chenshihong@sdu.edu.cn.
  • 3 School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, 250012, China. Electronic address: konglinghua@sdu.edu.cn.
  • 4 School of Basic Medical Sciences, The Second Hospital of Shandong University, Jinan, Shandong Province, 250012, China; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, 250012, China; Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: shuyanyu@sdu.edu.cn.
PMID: 40967008 DOI: 10.1016/j.redox.2025.103873
Abstract

Oxidative stress, defined as a process triggered by an imbalance between the accumulation of free radicals and antioxidant defences, has been considered implicated in many neurological disorders, including major depressive disorder (MDD). In the present study, we demonstrated that the expression of Phosphatase and actin regulatory factor 4 (Phactr4) was increased within the dentate gyrus (DG) region of the hippocampus of the chronic stress-induced depressive mice. Phactr4 has been shown to enhance oxidative stress in the brain by interacting with protein Phosphatase 1 (PP1) and synergistically reducing the level of phosphorylation of glycogen synthase kinase 3β (GSK3β), thus enhance the susceptibility to stress stimulation in mice. Knocking down phactr4 in the hippocampal DG regions can suppressed GSK3β activation, alleviate oxidative stress, and further improve the depression-like behaviors in mice. More interestingly, we further found physical exercise can downregulate the level of Phactr4, reduce the accumulation of Reactive Oxygen Species (ROS) in the brain, ameliorate neuronal damage, and reverse depressive-like behaviors in mice. These findings suggest that physical exercise may promote the restoration of oxidative stress in brain and ameliorates depressive behaviors in mice by down-regulating the Phactr4-PP1-GSK3β pathway.

Keywords

Depression; Exercise; GSK3β; Oxidative stress; Phactr4.

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