Lipocalin-2 and intestinal diseases

Table 1 Lipocalin-2 expression and its impact on disease pathogenesis

Organ/site	Disease	Outcome	Mechanism	Ref.
Eye	Retinal inflammation	Overexpression of LCN2 in RPE cells manifested protection from cell death	LCN2 induced expression of antioxidant enzymes HMOX1 and SOD2 in RPE cells and inhibited the cytotoxic effects of H2O2 and lipopolysaccharide	[120]
	Age-related macular degeneration	In RPE cells, elevated LCN2 expression disrupts autophagy, enhances inflammasome activity, induces oxidative stress, triggers ferroptosis, and exacerbates cellular damage, thereby impacting iron homeostasis	LCN2 forms a complex with ATG4B, designated as LCN2-ATG4B-LC3-II, modulating ATG4B activity and LC3-II lipidation to regulate autophagy	[121]
Brain	Cerebral ischemia/reperfusion injury	After stroke in mice with middle cerebral artery occlusion, astrocyte LCN2 levels surged within 24 hours. Mice lacking LCN2 had smaller infarcts and better neurocognitive recovery poststroke	24p3R inhibition reduced pyroptosis and pro-inflammatory cytokine secretion via LCN2, an effect reversed by Nigrostatin-induced NLRP3 activation. Pyroptosis in astrocytes was exacerbated by rLCN2 in Lcn2-/- mice	[122]
	Cancer brain metastasis	LCN2 drives neuroinflammation, promoting brain metastasis in melanoma and breast cancer	Signals from the primary tumor activate astrocytes, which attract immunosuppressive granulocytes to brain metastases, a process that increases LCN2 levels. Targeting LCN2 genetically reduces neuroinflammation and brain metastasis	[123]
	Neurodegenerative diseases	LCN2 in astrocytes can shift their state from neurotoxic to neuroprotective, possibly preventing neuronal death and halting neurodegenerative disease progression	Activated astrocytes secrete LCN2, which binds to the 24p3R receptor in an autocrine loop, further activating astrocytes through the NF-κB pathway	[124]
Kidney	Active lupus nephritis	Biomarker	LCN2 is highly secreted by renal tubular epithelial cells in response to various renal injuries, leading to elevated levels in blood and urine, and can serve as a biomarker for multiple kidney injuries and prognosis	[125]
	Acute kidney injury			[126]
	Kidney transplant			[127]
Liver	NASH	In patients with NASH, LCN2 expression was significantly associated with inflammation and fibrosis	LCN2 serves as a central mediator in hepatic stellate cell activation during leptin-deficient obesity, via the α-SMA/MMP9/STAT3 pathway, worsening NASH	[128]
			SREBP-1c mediates LCN2 expression, linking to NASH pathogenesis. SREBP-1c deletion downregulates LCN2, alleviating NASH severity. It also couples iron and lipid metabolism via LCN2, impacting NASH development	[129]
	Hepatocellular carcinoma	Elevated LCN2 expression promotes hepatocellular carcinoma cell proliferation	Targeting PGAM1 suppresses hepatocellular carcinoma growth by inhibiting LCN2 and PD-L1 expression through an energy stress/ROS-mediated reduction in AKT activity, thereby enhancing CD8+ T-cell infiltration	[71]
Pancreas	Pancreatic ductal adenocarcinoma	Overexpression of LCN2 markedly inhibits pancreatic cancer cell adhesion and invasion	LCN2 diminishes pancreatic cancer cell adhesion and invasion by partially suppressing focal adhesion kinase tyrosine-397 phosphorylation and inhibits angiogenesis by impeding VEGF production	[130]
		Lcn2 deficiency in PDAC mouse models retarded weight gain, adiposity, and tumor progression and enhanced survival	Pancreatic stromal cells, devoid of LCN2 synthesis, express the LCN2 receptor SLC22A17. LCN2 binding to SLC22A17 on cancer-associated fibroblasts stimulates secretion of inflammatory mediators and MMP9, enhancing immune cell infiltration and tumor progression in the pancreatic cancer microenvironment	[131]
Artery	Atherosclerosis	LCN2 enhances HDL metabolism and facilitates macrophage reverse cholesterol transport	LCN2 enhances HDL metabolism and attenuates atherogenesis by inhibiting Nedd4-1-mediated SR-BI ubiquitination at lysines 500 and 508	[132]
Bone	Osteoporosis	LCN2, acting as a downstream factor, induces iron overload in osteocytes, promoting their apoptosis	Repin1 knockdown reduced LCN2 expression, mitigating the toxic effects of intracellular iron overload	[133]
Other	Chronic stress	Peripheral and central inhibition of the LCN2 pathway significantly alleviated CRS-induced behavioral deficits	LCN2’s anxiogenic effects are linked to its modulation of neuronal activities in the medial prefrontal cortex. Under CRS, hepatic tissues are identified as the main source of serum LCN2, released via the vagal efferent pathway from the dorsal motor vagal nucleus	[134]

LCN2: Lipocalin-2; RPE: Retinal pigment epithelium; HMOX1: Heme oxygenase 1; SOD2: Superoxide dismutase-2; ATG4B: Autophagy-related gene 4B; NLRP3: NACHT, LRR, and PYD domains-containing protein 3; NF-κB: Nuclear factor-kappaB; NASH: Nonalcoholic steatohepatitis; α-SMA: Alpha-smooth muscle actin; MMP9: Matrix metallopeptidase 9; STAT3: Signal transducer and activator of transcription 3; PGAM1: Phosphoglycerate mutase 1; PD-L1: Programmed death-ligand 1; ROS: Reactive oxygen species; AKT: Protein kinase B; VEGF: Vascular endothelial growth factor; SLC22A17: Solute carrier family 22 member 17; PDAC: Pancreatic ductal adenocarcinoma; HDL: High-density lipoprotein; CRS: Chronic restraint stress.