Invest Clin 67(2): 168 - 177, 2026 https://doi.org/10.54817/IC.v67n2a01

Corresponding author: Yang Li. Department of Otorhinolaryngology Head and Neck Surgery, Ningbo Hospital of In-

tegrated Traditional Chinese and Western Medicine, Ningbo 315100, Zhejiang Province, China. Email: liyangny2h@

hosp-edu.cn

Expressions of Lipocalin-2 in nasal tissues

and secretions of patients with chronic

rhinosinusitis with nasal polyps and

correlations with inflammatory factors.

Yang Li, Youxiong Yang, Jun Xu and Yun Zhu

Department of Otorhinolaryngology Head and Neck Surgery, Ningbo Hospital

of Integrated Traditional Chinese and Western Medicine, Ningbo,

Zhejiang Province, China.

Keywords: Inflammation Mediators; Lipocalin-2; Nasal polyps; Rhinosinusitis.

Abstract. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common

inflammatory disease of the upper airway. Lipocalin-2, an inflammation-related

glycoprotein involved in innate immune regulation, has been linked to several

chronic inflammatory disorders, but its role in CRSwNP remains unclear. This

study aimed to examine the expression of Lipocalin-2 in nasal tissues and se-

cretions of CRSwNP patients and its relationship with inflammatory factors.

Seventy patients diagnosed with CRSwNP between January 2023 and January

2025 were enrolled in the case group, while 60 patients with simple nasal sep-

tal deviation served as controls. NP tissues and nasal secretions were collected

from CRSwNP patients, whereas inferior turbinate mucosal tissues and nasal

secretions were obtained from controls. Levels of Lipocalin-2, interleukin-5

(IL-5), IL-6, and tumor necrosis factor-alpha (TNF-α) were measured and ana-

lyzed. Compared with controls, CRSwNP patients showed significantly higher

levels of Lipocalin-2 and inflammatory cytokines in nasal secretions (p<0.05).

Stratification based on Visual Analog Scale (VAS) scores and computed tomog-

raphy Lund-Mackay (CT L-M) scores indicated that these markers were notably

higher in the moderate-to-severe group than in the mild disease group (p<

0.05). Lipocalin-2 was positively correlated with IL-5, IL-6, TNF-α, as well as

VAS, Lund-Kennedy endoscopy, and CT L-M scores (all p<0.05). In summary,

Lipocalin-2 is highly expressed in nasal polyp tissues and secretions of CRSwNP

patients and closely associated with inflammatory cytokine levels and clinical

severity, implying its potential as a biomarker for disease activity in CRSwNP.

Role of Lipocalin-2 in chronic rhinosinusitis 169

Vol. 67(2): 168 - 177, 2026

Expresión de Lipocalina-2 en los tejidos nasales y secreciones

de pacientes con rinosinusitis crónica con pólipos nasales

y su correlación con factores inflamatorios.

Invest Clin 2026; 67 (2): 168 – 177

Palabras clave: Mediadores de Inflamación; Lipocalina 2; Pólipos Nasales; Rinosinusitis.

Resumen. La rinosinusitis crónica con pólipos nasales (CRSwNP) es una

enfermedad inflamatoria frecuente de las vías respiratorias superiores. La li-

pocalina-2, una glicoproteína asociada a la inflamación e implicada en la re-

gulación de la inmunidad innata, se ha relacionado con diversas enfermedades

inflamatorias crónicas; sin embargo, su papel en la CRSwNP aún no ha sido

completamente aclarado. El objetivo de este estudio fue investigar la expresión

de la lipocalina-2 en los tejidos y en las secreciones nasales de pacientes con

CRSwNP, así como su asociación con factores inflamatorios. Setenta pacientes

diagnosticados con CRSwNP entre enero de 2023 y enero de 2025 fueron inclui-

dos en el grupo de casos, mientras que 60 pacientes con desviación simple del

tabique nasal sirvieron como grupo control. Se recogieron tejidos de pólipos

nasales y secreciones nasales de los pacientes con CRSwNP, mientras que en

los controles se obtuvieron tejidos de la mucosa del cornete inferior y secrecio-

nes nasales. Se midieron y analizaron los niveles de lipocalina-2, interleucina-5

(IL-5), interleucina-6 (IL-6) y del factor de necrosis tumoral alfa (TNF-α). En

comparación con los controles, los pacientes con CRSwNP presentaron niveles

significativamente elevados de lipocalina-2 y citocinas inflamatorias en las se-

creciones nasales (p<0,05). La estratificación basada en la escala visual analó-

gica (VAS) y en las puntuaciones de la tomografía computarizada Lund-Mackay

(CT L-M) mostró que estos marcadores eran notablemente más altos en el

grupo con enfermedad moderada a grave que en el grupo con enfermedad leve

(p<0,05). La lipocalina-2 se correlacionó positivamente con IL-5, IL-6 y TNF-α,

así como con las puntuaciones de VAS, Lund-Kennedy endoscópica y CT L-M

(todas con p<0,05). En conclusión, la lipocalina-2 se expresa de forma elevada

en los tejidos de los pólipos nasales y en las secreciones nasales de pacientes

con CRSwNP, y se asocia estrechamente con los niveles de citocinas inflamato-

rias y la gravedad clínica, lo que sugiere su posible utilidad como biomarcador

de la actividad de la enfermedad en la CRSwNP.

Received: 30-07-2025 Accepted: 20-02-2026

INTRODUCTION

Chronic rhinosinusitis with nasal polyps

(CRSwNP) is a common nasal disease char-

acterized by ongoing inflammation and pol-

ypoid hyperplasia in the nasal cavity or sinus

mucosa, often accompanied by bone dam-

age and mucus retention 1. The incidence

of CRS in China is approximately 8%, with

CRSwNP patients making up about one-third

of the total cases 2. CRSwNP has a complex

cause involving infection, environmental fac-

tors, allergies, and several other elements,

with clinical signs like purulent nasal dis-

170 Li et al.

Investigación Clínica 67(2): 2026

charge, nasal blockage, and reduced sense

of smell, which seriously impact patients’

quality of life 3. In clinical treatment, manag-

ing CRSwNP mainly involves medication and

surgery, but the disease is often persistent

and prone to recurrence due to factors such

as low immunity, recurrent infections, and

the limited precision of current therapies 4.

The rate of recurrence after surgical removal

can be as high as 40-60% 5. Therefore, it is

particularly important to explore new diag-

nostic and therapeutic targets for CRSwNP

to improve patient outcomes.

As a secretory glycoprotein isolated

from neutrophils in the early stage, Lipo-

calin-2 has the typical β-barrel structure of

the lipocalin family and participates in many

physiological processes, including iron me-

tabolism, cytokine secretion, and extracel-

lular trap regulation through binding to

various ligands and receptors. It is also clear

that Lipocalin-2 plays a crucial role in tumor

cell proliferation and apoptosis, as well as in

chronic inflammatory responses 6. In inflam-

matory diseases such as asthma and atopic

dermatitis, the widespread expression of Li-

pocalin-2 is positively associated with eosin-

ophil counts and inflammatory factor levels,

indicating its strong potential as a target for

disease risk 7. However, systematic clinical

studies on the expression pattern of Lipocal-

in-2 in CRSwNP nasal tissues and secretions,

and the mechanisms through which it cor-

relates with inflammatory factors, including

interleukin-5 (IL-5) and IL-6, have not yet

been conducted.

Given this, an in-depth analysis was

conducted on the relationship between Li-

pocalin-2 expression levels and the charac-

teristics of nasal tissues and secretions from

CRSwNP patients, and its correlations with

inflammatory factors were explored in the

present study.

PATIENTS AND METHODS

Subjects

Seventy patients diagnosed with

CRSwNP and visiting our hospital from Janu-

ary 2023 to January 2025 were included in

the case group. Additionally, a control group

(n=60) consisting of patients with simple

nasal septal deviation was established. De-

mographic and clinical characteristics, such

as sex, age, body mass index, and comorbid

allergic rhinitis, are summarized in Table 1.

There were no statistically significant differ-

ences in baseline characteristics between

the two groups (p>0.05).

Inclusion criteria were as follows: (1)

patients in the case group diagnosed with

CRSwNP through examinations showing

clinical signs, rhinoscopy, and computed to-

mography (CT), and treated with functional

endoscopic sinus surgery; (2) individuals in

the control group meeting the diagnostic cri-

teria for nasal septum deviation as specified

in the Volume of Otolaryngology Head and

Neck Surgery Clinical Practice Guidelines8,

without NP or sinusitis based on clinical

examinations; and (3) patients aged 18-65

years. The following exclusion criteria were

Table 1. General data of patients.

Group n Gender

(male/female)

Age

(year)

Body mass index

(kg/m2)

Comorbid allergic

rhinitis (n)

Case 70 40/30 42.39±10.24 22.97±2.01 28 (40.00%)

Control 60 36/24 41.92±10.46 22.67±1.97 40 (66.67%)

χ2/t 0.109 0.258 0.856 0.617

p 0.742 0.797 0.394 0.432

Data are presented as mean ± standard deviation (SD) or number (percentage). Comparisons between groups were

performed using the independent-samples t-test for continuous variables and the chi-square (χ2) test for categorical

variables. A p value < 0.05 was considered statistically significant.

Role of Lipocalin-2 in chronic rhinosinusitis 171

Vol. 67(2): 168 - 177, 2026

applied: (1) patients who had been treated

with a large amount of antibiotics, immuno-

suppressants, or antihistamines in the past

month; (2) those with severe cardiac or pul-

monary diseases or coagulation disorders;

(3) individuals with strict surgical contrain-

dications; (4) those complicated by fungal

sinusitis, asthma, or nasal cavity neoplasm;

and (5) individuals with serious psychiatric

or psychological disorders or who cannot

communicate normally. This study was re-

viewed and approved by the ethics commit-

tee of Ningbo Yinzhou No. 2 Hospital, and all

patients in both groups signed the informed

consent form.

Sample collection and treatment

During surgery, nasal polyps (NP) tis-

sues and nasal secretions were collected

from the case group, while inferior turbinate

mucosal tissues and nasal secretions were

obtained from the control group. NP tissues:

The harvested samples were immediately

rinsed with 4°C normal saline to remove

blood clots and surface impurities. Then, the

samples were cut into two tissue blocks of

similar size and volume using a sterile scal-

pel. One tissue block was immersed in 10%

(v/v) formalin solution for 12-24 hours for

fixation, then embedded in wax. The other

was placed in a sterile cryotube for 1-3 hours

and then frozen in liquid nitrogen for later

use. Nasal secretions: An aseptic cotton

swab or cotton pad was gently rotated deep

into the nasal cavity and NP for 15 minutes

to obtain at least 2 mL of secretions. These

were processed in an H1850 centrifuge (Hu-

nan Xiangyi Laboratory Instrument Develop-

ment Co., Ltd.) at 3,000 rpm for 10 minutes.

The supernatant was aspirated and stored in

a -80°C freezer.

Detection of Lipocalin-2 and inflamma-

tory factors

Lipocalin-2 expression in tissues: The

sections, dipped and embedded in wax, were

sequentially hydrated in ethanol and xylene

of varying concentrations. Following deparaf-

finization, a high-temperature, high-pressure

retrieval method was used to expose cell

and tissue antigens, and a hydrogen perox-

ide blocking solution was added in drops to

inhibit peroxidase activity. Next, goat serum

was added dropwise, followed by a 10-min-

ute incubation at room temperature; the

supernatant was discarded, and a Lipocalin-

2-specific primary antibody was added for

overnight incubation at 4°C. The next day,

streptavidin-biotin-peroxidase complex solu-

tion was added dropwise and incubated for

15 minutes at room temperature, followed by

color development with DAB solution, obser-

vation under an optical microscope (400×),

rinsing, and counterstaining with hematoxy-

lin. Afterward, the sections were placed in an

alkaline solution until they turned blue, de-

hydrated in a graded alcohol series, cleared

in xylene, and mounted with neutral resin

added dropwise.

The expression levels of Lipocalin-2 in

nasal tissues, as well as Lipocalin-2 and in-

flammatory factors [interleukin-5 (IL-5),

IL-6, and tumor necrosis factor-α (TNF-α)]

in nasal secretions, were quantified us-

ing an ELISA kit (Shanghai Fengshou Bio-

technology Co., Ltd.) strictly following the

manufacturer’s instructions. Specifically,

nasal tissue samples were homogenized and

processed for ELISA-based measurement of

Lipocalin-2, while nasal secretion samples

were centrifuged at 300× g at 4°C for 10

minutes; the supernatant was then collected

and stored at -80°C in aliquots for testing.

Before testing, the kit was brought to room

temperature for 30 minutes, and the wash-

ing solution (diluted using distilled water at

1:20) and sample diluent [phosphate-buff-

ered saline with Tween-20 (PBST) contain-

ing 1% bovine serum albumin (BSA)] were

prepared. Next, the standard substance was

serially diluted (e.g., Lipocalin-2 standard

range: 156-10,000 pg/mL). Then, 100 μL of

each sample and standard (nasal secretion

supernatants pre-diluted with sample dilu-

ent at 1:2-1:10 as needed) were added to a

microtiter plate pre-coated with specific an-

172 Li et al.

Investigación Clínica 67(2): 2026

tibodies (polyclonal antibody for Lipocalin-2

measurement), followed by incubation at

37°C for 90 minutes and 3 washes with PBST

after discarding the liquid (allowing the

plate to stand for 30 seconds after each fill-

ing, then pat dry). Subsequently, each well

was blocked with 200 μL of blocking solu-

tion (5% skim milk or 1% BSA/PBS) at 37°C

for 2 hours and washed 3 times. Afterward,

100 μL of biotin-labeled detecting antibod-

ies (diluted as specified in the instructions)

were added, incubated at 37°C for 60 min-

utes, and washed 5 times (samples with high

background could be washed up to 7 times).

Then, 50 μL of TMB chromogenic substrate

(A/B solution, 50 μL each) was added for

room temperature development, protected

from light, for 15 minutes or until positive

wells turned light blue. Next, 50 μL of 2 M

H₂SO₄ stop buffer was added to each well,

and the absorbance (optical density, OD)

was immediately measured at 450 nm, with

a reference wavelength of 630 nm, using a

microplate reader. Finally, target factor con-

centrations were calculated using the stan-

dard curve (four-parameter logistic regres-

sion fitting, R² > 0.99), with a CV value of

less than 15% among replicate wells.

Assessment of disease severity

A visual analog scale (VAS) was used for

the quantitative evaluation of four clinical

symptoms in patients, namely nasal obstruc-

tion 9, runny nose, hyposmia, and dizziness

and headache. Each item was scored on a 0-2

scale, with a total of 10 points; higher scores

indicated more severe symptoms. Addition-

ally, the Lund-Kennedy nasal endoscopy (L-K)

score was used to quantify dimensions such

as NP area 10, secretions, mucosal edema,

and scars, with each item scored 0-2 points

and a total score of 0-12 points. The higher

the scores, the greater the NP load and the

higher the disease activity. Furthermore, the

Lund-MacKay sinus computed tomography

(L-M) score was applied for standardized scor-

ing based on patients’ computed tomography

(CT) imaging results 11, where the inflamma-

tion in the maxillary sinus, ethmoidal sinus,

frontal sinus, and sphenoidal sinus on both

sides and the degree of ostiomeatal complex

obstruction in patients were mainly observed.

Each item was scored 0-2 points, and the to-

tal score was 0-24 points, with higher scores

representing a wider range of inflammation

and a higher degree of the disease.

Statistical analysis

SPSS 24.0 software was adopted for sta-

tistical analysis. Measurement data in line

with normal distribution were expressed by

( ± s) and compared between groups via the

independent-samples t-test. Count data were

represented as [n (%)] and subjected to the χ2

test for intergroup comparison. The correla-

tions of the expression levels of Lipocalin-2,

IL-5, IL-6, and TNF-α with the VAS, L-K, and

CT L-M scores were identified through Pear-

son’s correlation analysis. p<0.05 denoted a

statistically significant difference.

RESULTS

Lipocalin-2 expression levels in nasal tissues

The expression level of Lipocalin-2 in

nasal tissues was significantly higher in the

case group than in the control group (p

<0.05) (Table 2).

Table 2. Lipocalin-2 expression levels

in nasal tissues.

Group n Lipocalin-2 (ng/mL)

Case 70 50.36±16.24

Control 60 26.19±9.21

t10.204

p <0.001

Data are presented as mean ± standard deviation

(SD). Comparisons between groups were performed

using the independent-samples t-test.

Levels of Lipocalin-2 and inflammatory

factors in nasal secretions from the two

groups

The case group showed higher levels of

Lipocalin-2, IL-5, IL-6, and TNF-α in nasal

Role of Lipocalin-2 in chronic rhinosinusitis 173

Vol. 67(2): 168 - 177, 2026

secretions compared to the control group,

and these differences were statistically sig-

nificant (p<0.05) (Table 3).

Correlation between Lipocalin-2 and

inflammatory factors in nasal secretions

obtained from the case group

Pearson’s correlation analysis revealed

that Lipocalin-2 had positive correlations

with IL-5, IL-6, and TNF-α in nasal secretions

from the case group (p<0.05) (Table 4).

Levels of Lipocalin-2 and inflammatory

factors in the case group with different

disease severities

Based on the stratification using the

VAS score (≤5 points for mild and >5 points

for moderate-to-severe) and CT L-M score

(≤12 points for mild-to-moderate and >12

points for severe), all indicators were sig-

nificantly higher in the moderate-to-severe

group compared to the mild group (p<

0.05) (Table 5).

Correlations of Lipocalin-2 and

inflammatory factors with disease severity

in the case group

In the case group, the VAS, L-K, and CT

L-M scores were positively correlated with

the expression levels of Lipocalin-2 and in-

flammatory factors in patients (p<0.05)

(Table 6).

DISCUSSION

Classified as an inflammatory disease

of the upper respiratory tract secondary to

CRS subtypes, CRSwNP is partially caused

by abnormal anatomy, genetics, allergic ede-

ma, and other factors, with characteristic

changes such as inflammatory cell infiltra-

tion, stromal edema, and NP growth. Clini-

cally, it manifests as recurrent dizziness and

headache, sinus ostium blockage, purulent

nasal discharge, and anosmia 12,13. Although

immune responses dominated by T helper

type 2 (Th2) inflammation are considered

the main drivers of pathological imbalance

in CRSwNP, the biological targets that regu-

late inflammatory factor expression levels

remain undefined 14. Lipocalin-2 is a pro-

inflammatory, iron-shuttle molecule associ-

ated with neutrophil gelatinase. It partici-

pates in biological processes including cell

differentiation, apoptosis, defense against

bacterial infections, and fatty acid transpor-

tation. It also plays a crucial role in iron me-

tabolism, oxidative stress, and inflammation

regulation in the human body 15. A recent

study found that Lipocalin-2 can predict

and reflect the degree of renal function im-

Table 3. Levels of Lipocalin-2 and inflammatory factors in nasal secretions.

Group n Lipocalin-2 (ng/mL) IL-5 (pg/mL) IL-6 (pg/mL) TNF-α (pg/mL)

Case 70 62.15±14.26 46.92±4.52 58.36±14.21 113.68±9.14

Control 60 24.69±8.19 25.64±3.24 43.69±10.24 95.49±8.36

t17.961 30.380 6.651 11.764

p<0.001 <0.001 <0.001 <0.001

Data are presented as mean ± standard deviation (SD). Comparisons between groups were performed using the

independent-samples t-test. Interleukin-5 (IL-5), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α).

Table 4. Correlation between Lipocalin-2 and

inflammatory factors in nasal secretions from

the case group.

Inflammatory factor Lipocalin-2

IL-5 0.827 <0.001

IL-6 0.465 <0.001

TNF-α0.597 <0.001

Interleukin-5 (IL-5), interleukin-6 (IL-6), tumor ne-

crosis factor-alpha (TNF-α). r indicates Pearson’s co-

rrelation coefficient.

174 Li et al.

Investigación Clínica 67(2): 2026

pairment, offering clinical advantages like

early monitoring, easy assessment, and high

specificity 16. As previously researched, Li-

pocalin-2 is a key player in the pathology of

diseases such as alcoholic fatty liver and ma-

lignant tumors. It promotes disease progres-

sion by regulating inflammatory expression,

mediating iron homeostasis, and participat-

ing in signaling pathways, making it a poten-

tial target for diagnosis and prevention 17.

However, studies on Lipocalin-2 and inflam-

matory factors in CRSwNP are still limited.

In this study, the case group exhibited

significant increases in the expression level

of Lipocalin-2 in nasal tissues as well as the

levels of Lipocalin-2, IL-5, IL-6, and TNF-α

in nasal secretions, in contrast to the con-

trol group, suggesting that Lipocalin-2 and

inflammatory factors are highly expressed

in the pathogenesis of CRSwNP, exerting

a synergistic effect on NP formation. As a

multifunctional pro-inflammatory protein,

Lipocalin-2 induces the expression of che-

mokines, including CXCL8 and CCL2, and

recruits neutrophils and eosinophils to NP

tissues in combination with Th2 inflamma-

tory factors such as IL-5, thereby exacer-

bating inflammatory infiltration. Moreover,

TNF-α, IL-6, and other inflammatory fac-

tors can activate T lymphocytes to mediate

neutrophil secretion of Lipocalin-2, form a

synergistic cycle of inflammatory factors

Table 5. Levels of Lipocalin-2 and inflammatory factors in the case group

with different disease severities.

Stratification indicator n Lipocalin-2 (ng/

mL) IL-5 (pg/mL) IL-6 (pg/mL) TNF-α (pg/mL)

VAS score

≤5 points (mild) 25 48.21±12.35 40.23±3.89 52.14±11.56 105.32±8.23

>5 points (moderate-to-severe) 45 66.89±15.42 51.26±4.71 62.89±13.24 118.97±9.56

t5.196 9.964 3.401 6.005

p<0.001 <0.001 0.001 <0.001

CT L-M score

≤12 points (mild-to-moderate) 32 52.36±13.18 43.56±4.12 55.21±12.34 108.65±8.78

>12 points (severe) 38 68.92±14.89 50.12±4.98 61.54±11.87 119.23±9.01

t4.639 5.602 2.108 4.750

p<0.001 <0.001 0.039 <0.001

Data are presented as mean ± standard deviation (SD). Comparisons between subgroups were performed using the

independent-samples t-test. Interleukin-5 (IL-5), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α). Visual

analog scale (VAS), Lund-MacKay sinus computed tomography (CT L-M).

Table 6. Correlations of Lipocalin-2 and inflammatory factors with disease severity in the case group.

Group Lipocalin-2 IL-5 IL-6 TNF-α

r p r p r p r p

VAS score 0.756 <0.001 0.613 <0.001 0.619 <0.001 0.078 <0.001

L-K score 0.647 <0.001 0.519 0.003 0.492 <0.001 0.069 0.004

CT L-M score 0.597 0.002 0.616 <0.001 0.473 <0.001 0.064 <0.001

r indicates Pearson’s correlation coefficient. Correlation analyses were performed using Pearson correlation analy-

sis. Interleukin-5 (IL-5), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α). Visual analog scale (VAS),

Lund-Kennedy nasal endoscopy (L-K), Lund-MacKay sinus computed tomography (CT L-M).

Role of Lipocalin-2 in chronic rhinosinusitis 175

Vol. 67(2): 168 - 177, 2026

and Lipocalin-2, and enhance the release of

inflammatory signals 18. The iron-chelating

function of Lipocalin-2 can activate the fer-

roptosis pathway, disrupt the metabolic

stability of the nasal mucosa, and elevate

intracellular ferrous ion concentration. Be-

sides, inflammatory factors released under

oxidative stress activate the NF-κB signal-

ing pathway, which up-regulates the expres-

sion of inflammatory factors and Lipocalin-2

again 19. In addition, owing to its specific

structure, Lipocalin-2 is capable of binding

to and transporting various lipophilic small

molecules including iron and fatty acids, af-

fecting the metabolism of immune cells and

polarization of macrophages. Finally, it col-

laborates with Th2 inflammatory factors to

induce epithelial-mesenchymal transition,

promote excessive deposition of the fibrous

extracellular matrix, and facilitate hyperpla-

sia and invasion of NP tissues. As indicated

in the literature, in the diseased skin tissues

of patients with psoriasis, keratinocytes ex-

hibit high Lipocalin-2 expression within an

activated inflammatory microenvironment,

and Lipocalin-2 has synergistic effects with

the pro-inflammatory factors TNF-α and IL-

8. Once again, it demonstrates the regula-

tory roles of Lipocalin-2 and inflammatory

factors in the disease validation cascade 20.

Through deep investigation, it was uncov-

ered that Lipocalin-2 had positive relations

to IL-5, IL-6, and TNF-α, together with sig-

nificantly positive correlations with the VAS,

L-K, and CT L-M scores in CRSwNP patients,

suggesting that Lipocalin-2 forms a patho-

genic network with inflammatory factors to

jointly participate in and reflect the progres-

sion of CRSwNP. Combined with correlation

analysis results, as a crucial cytokine regu-

lating eosinophil maturation, activation,

and tissue migration, IL-5 can work with

Lipocalin-2 to recruit eosinophils, transfer

them to NP tissues, and release toxic pro-

teins to aggregate local mucosal edema and

inflammation, resulting in increased NP size

and thickened sinus mucosa, and trigger-

ing symptoms such as nasal obstruction and

headache. TNF-α and IL-6 form a two-way

feedback loop with Lipocalin-2 that continu-

ously activates inflammation-related signal-

ing pathways and accelerates the release of

inflammatory mediators such as reactive

oxygen species and proteases, thereby up-

regulating ICAM-1 and other adhesion mol-

ecules, increasing vascular permeability of

the nasal mucosa, and amplifying inflamma-

tory responses. Meanwhile, Lipocalin-2 may

exacerbate pain sensitization by activating

trigeminal nerve endings in the nasal mu-

cosa and promoting the release of neuroin-

flammatory substances, which directly affect

the severity of the patient’s subjective symp-

toms as measured by the VAS score. Existing

studies have corroborated a positive corre-

lation between Lipocalin-2 expression levels

and the severity of ankylosing spondylitis 21.

In a study of hemorrhagic fever with renal

syndrome, Lipocalin-2 is highly expressed

in the serum of patients 22. As demonstrat-

ed by the above literature and the present

study, Lipocalin-2 is likely a broad-spectrum

regulator of chronic inflammatory diseases,

and its synergistic effects with inflammatory

factors may serve as a potential indicator of

clinical phenotypes and disease severity.

In conclusion, Lipocalin-2 exhibits

high expression in NP tissues and secre-

tions from CRSwNP patients, and it is not

only significantly correlated with levels

of inflammatory factors IL-5, IL-6, and

TNF-α, but also positively associated with

disease severity. This suggests that Lipo-

calin-2 could become a novel therapeutic

target for monitoring disease progression,

exploring the pathogenesis, and develop-

ing new treatments for CRSwNP. However,

this study only identified a correlation

between Lipocalin-2 and inflammatory

factors, and there is a lack of scientific

evidence regarding its regulatory mecha-

nisms and signaling pathways, which can

be examined in future research using cell

models or animal studies.

176 Li et al.

Investigación Clínica 67(2): 2026

Acknowledgements

None.

Funding

None.

ORCID ID of the authors

• Yang Li (YL):

0009-0000-9633-8038

• Youxiong Yang (YY):

0009-0007-3967-2559

• Jun Xu (JX):

0009-0003-8658-8537

• Yun Zhu (YZ):

0009-0008-7955-5530

Author’s contributions

YL designed this study and significantly

revised the paper; YY, JX, and YZ performed

this study, analyzed the data, and drafted the

paper. All authors have approved the submis-

sion and publication of this paper.

Conflict of interest

The authors declare no conflict of interest.

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