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. 2026 Feb 25;63(1):469.
doi: 10.1007/s12035-026-05737-8.

Hippocampal Neuronal Ferroptosis Driven by Lipocalin-2 Mediates Comorbid Visceral Pain and Anxiety in Irritable Bowel Syndrome

Ying Tang  1 , Zhengqing He  1 , Qianli Zhang  1 , Yiqian Liu  1 , Lu Li  1 , Yu Chen  2 , Aiqin Chen  3 , Chun Lin  4
Affiliations

Hippocampal Neuronal Ferroptosis Driven by Lipocalin-2 Mediates Comorbid Visceral Pain and Anxiety in Irritable Bowel Syndrome

Ying Tang et al. Mol Neurobiol. .

Abstract

Irritable bowel syndrome (IBS) is characterized by chronic visceral pain and anxiety comorbidity, yet the central mechanisms linking gut signals to persistent pain-emotion dysregulation remain unclear. This study investigated whether hippocampal Lipocalin-2 (LCN2) drives neuronal ferroptosis to mediate visceral hypersensitivity and anxiety-like behaviors in a neonatal rat IBS model. Using a colorectal distension model, we conducted behavioral tests, molecular assays, and electron microscopy. IBS-like rats exhibited upregulated hippocampal LCN2 expression, predominantly in neurons, alongside ferroptosis hallmarks including increased ACSL4, decreased GPX4, elevated Fe2⁺ and MDA levels, and mitochondrial damage. Inhibition of ferroptosis reversed visceral pain and anxiety-like behaviors. LCN2 knockdown in the hippocampal CA1 region alleviated IBS-related phenotypes, while LCN2 overexpression in normal rats induced similar behavioral and ferroptotic changes. These findings identify a novel LCN2-ferroptosis axis in hippocampal neurons that critically mediates gut-brain dysregulation in IBS. Our study provides the first causal evidence linking LCN2-driven ferroptosis to visceral pain-anxiety comorbidity, offering new mechanistic insights and potential therapeutic targets for IBS and related gut-brain disorders.

Keywords: Anxiety; Ferroptosis; Gut–brain axis; Hippocampus; Irritable bowel syndrome; Lipocalin-2.

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Conflict of interest statement

Declarations. Ethics Approval: The experimental protocol regarding animals was reviewed and approved by the Animal Welfare & Ethics Committee of Fujian Medical University (FJMU-IACUC-2023-Y-1044). Consent to Participate: Not applicable Consent for Publication: Not applicable Conflict of interest: The authors declare no competing interests.

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