2. Academic Validation
  3. Ferroplasticity drives social isolation-induced anxiety via a ventral hippocampal iron-α-synuclein axis

Ferroplasticity drives social isolation-induced anxiety via a ventral hippocampal iron-α-synuclein axis

  • Cell Metab. 2026 Jan 27:S1550-4131(25)00586-8. doi: 10.1016/j.cmet.2025.12.022.
Zhuo Wang 1,  Sifan Yang 2,  Tianrong Huang 3,  Jinhui Zhao 4,  Shuangyi Tan 4,  Yuhan Zhang 4,  Tianming Lü 5,  Pingming Qiu 6,  Junxia Min 7,  Fudi Wang 8
Affiliations

Affiliations

  • 1 Innovation Centre of Ministry of Education for Development and Diseases, the Sixth Affiliated Hospital (Nanhai District People's Hospital of Foshan), School of Medicine, South China University of Technology, Guangzhou 510006, China. Electronic address: [email protected].
  • 2 Innovation Centre of Ministry of Education for Development and Diseases, the Sixth Affiliated Hospital (Nanhai District People's Hospital of Foshan), School of Medicine, South China University of Technology, Guangzhou 510006, China; The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China; Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun 130021, China.
  • 3 Department of Neurology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.
  • 4 Innovation Centre of Ministry of Education for Development and Diseases, the Sixth Affiliated Hospital (Nanhai District People's Hospital of Foshan), School of Medicine, South China University of Technology, Guangzhou 510006, China.
  • 5 Department of Neurology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China. Electronic address: [email protected].
  • 6 School of Forensic Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
  • 7 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
  • 8 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China; Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun 130021, China. Electronic address: [email protected].
PMID: 41605214 DOI: 10.1016/j.cmet.2025.12.022
Abstract

Social isolation is a major environmental driver of anxiety disorders, yet its neurobiological underpinnings remain elusive. We report here that social isolation triggers "ferroplasticity"-a novel form of experience-dependent synaptic remodeling-in ventral hippocampus (vHip) pyramidal neurons via a glucocorticoid-initiated iron-α-synuclein (α-Syn) axis. Psychosocial stress specifically engages this pathway. Mechanistically, isolation-induced Glucocorticoid Receptor activation upregulates Transferrin Receptor 1 (TfR1), leading to neuronal iron accumulation, which boosts α-Syn expression via translational derepression. α-Syn then enhances glutamate release and spine density, driving vHip hyperexcitability and anxiety. Interventions targeting the TfR1-iron-α-Syn axis at any node prevent or reverse anxiety-like behaviors, establishing necessity and causality. Translationally, intranasal delivery of an iron chelator or α-Syn-targeting antisense oligonucleotide (ASO) normalizes vHip neural activity and alleviates anxiety, highlighting a direct and viable path to clinical translation. Our findings define ferroplasticity as a core mechanism in social stress pathology, bridging brain iron metabolism with affective disorders.

Keywords

anxiety; ferroplasticity; glucocorticoid receptor; iron homeostasis; social isolation; transferrin receptor 1; α-synuclein.

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