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

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.