Lipocalin-2 Functions in Inflammation and Disease

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin, is a 25-kDa secreted glycoprotein that plays pivotal roles in innate immunity, iron homeostasis and cell signalling. Rapidly induced by pro-inflammatory stimuli such as interleukin-1β, tumour necrosis factor-α and interleukin-17 via NF-κB and STAT1 pathways, LCN2 is produced by neutrophils, epithelial cells, hepatocytes, adipocytes and glial cells under stress or injury. In the circulation, it binds siderophores to limit microbial iron acquisition and modulates matrix metalloproteinase-9 activity, thereby influencing tissue remodelling. In the central nervous system, astrocyte- and microglia-derived LCN2 drives neuroinflammation and excitotoxicity, contributing to neurodegenerative disorders and stroke pathology. Peripheral overproduction of LCN2 links obesity and cardiomyopathy through iron-mediated apoptosis of cardiomyocytes. In cancer, LCN2 promotes tumour progression and metastasis by stabilising EGFR and enhancing its recycling, as well as by sustaining angiogenesis. Clinically, elevated LCN2 levels serve as biomarkers for acute kidney injury, cardiovascular events and chronic inflammatory states. Emerging strategies to modulate LCN2 include neutralising antibodies, receptor antagonists, autophagy induction and RNA interference, underscoring its therapeutic potential across a spectrum of inflammatory and proliferative diseases.

Research from Nature Portfolio

Recent studies have revealed that chronic stress elicits a hepatic-to-brain axis in which hepatocytes upregulate LCN2 via sympathetic innervation. Elevated circulating LCN2 crosses the blood-brain barrier and alters neuronal excitability in the medial prefrontal cortex, precipitating anxiety-like behaviours in murine models. Genetic ablation or pharmacological reduction of LCN2 attenuates stress-induced behavioural deficits, highlighting a novel neuroimmune pathway and identifying LCN2 as a mediator of psycho-immune interactions.

Lipocalin-2 Functions in Inflammation and Disease publication trend

The graph below shows the total number of articles in lipocalin-2 functions in inflammation and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Lipocalin-2 (LCN2): A secreted glycoprotein involved in iron binding, immune defence and cell signalling.

NF-κB: A transcription factor complex that regulates genes involved in inflammation and immune responses.

NLRP3 inflammasome: A multiprotein cytosolic complex that activates inflammatory caspases and cytokine release.

Pyroptosis: A pro-inflammatory form of programmed cell death characterised by pore formation and cytokine secretion.

Autophagy: A cellular degradation pathway that delivers cytoplasmic contents to lysosomes for recycling.

24p3R: The cell-surface receptor for LCN2 that mediates iron transport and signalling effects.

References

1. Stress increases hepatic release of lipocalin 2 which contributes to anxiety-like behavior in mice. Nature Communications (2024).
2. Lipocalin-2: a therapeutic target to overcome neurodegenerative diseases by regulating reactive astrogliosis. Experimental & Molecular Medicine (2023).
3. Silencing LCN2 suppresses oral squamous cell carcinoma progression by reducing EGFR signal activation and recycling. Journal of Experimental & Clinical Cancer Research (2023).
4. Prognostic utility of neutrophil gelatinase-associated lipocalin (NGAL) levels for cardiovascular events in patients with stable coronary artery disease treated with percutaneous coronary intervention: a prospective longitudinal cohort study. Biomarker Research (2025).
5. Lipocalin-2-mediated astrocyte pyroptosis promotes neuroinflammatory injury via NLRP3 inflammasome activation in cerebral ischemia/reperfusion injury. Journal of Neuroinflammation (2023).
6. Biological Functions and Therapeutic Potential of Lipocalin 2 in Cancer. International Journal of Molecular Sciences (2020).
7. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. Journal of Biological Chemistry (1993).
8. The High Molecular Weight Urinary Matrix Metalloproteinase (MMP) Activity Is a Complex of Gelatinase B/MMP-9 and Neutrophil Gelatinase-associated Lipocalin (NGAL) MODULATION OF MMP-9 ACTIVITY BY NGAL*. Journal of Biological Chemistry (2001).
9. Induction of Neutrophil Gelatinase-associated Lipocalin Expression by Co-stimulation with Interleukin-17 and Tumor Necrosis Factor-α Is Controlled by IκB-ζ but neither by C/EBP-β nor C/EBP-δ*. Journal of Biological Chemistry (2010).
10. Lipocalin-2 Induces Cardiomyocyte Apoptosis by Increasing Intracellular Iron Accumulation*. Journal of Biological Chemistry (2011).
11. The Induction of Lipocalin-2 Protein Expression in Vivo and in Vitro *. Journal of Biological Chemistry (2014).