Chronic rhinosinusitis with nasal polyp (CRSwNP) is a chronic inflammatory disease characterized by epithelial remodeling. This study aimed to investigate the role of peroxiredoxin 2 (PRDX2) in CRSwNP and its potential mechanisms.
Methods
Proteomics analysis was conducted on nasal tissues from CRSwNP patients and healthy controls. Top-rank differentially expressed proteins were validated by immunofluorescence (IF) staining and reverse transcription quantitative-polymerase chain reaction (RT-PCR). In vitro experiments validated the effects and regulatory mechanisms of PRDX2 on nasal epithelial remodeling.
Results
Proteomics results revealed a disease-specific protein expression profile in CRSwNP polyp tissues, with DEGs primarily associated with oxidative stress. Our validation results demonstrated elevated reactive oxygen species (ROS) levels in CRSwNP with predominant accumulation in the nasal epithelium. Among these DEGs, PRDX2 was the most significantly downregulated, which was further confirmed by RT-PCR and IF. Moreover, PRDX2 was primarily expressed in nasal epithelial cells (NECs). RT-PCR results indicated that tissue PRDX2 expression was positively correlated with E-cadherin and negatively correlated with TGF-β1 and Vimentin expression in CRSwNP. In vitro experiments demonstrated that H2O2 stimulation promoted ROS and epithelial-mesenchymal transition (EMT) in NECs, while PRDX2 overexpression (OE) mitigated these effects. Furthermore, PRDX2 OE suppressed the H2O2-induced activation of the TGF-β1/SMAD signaling pathway, which plays a crucial role in regulating EMT in NECs.
Conclusion
Our findings suggest that the accumulation of ROS plays a critical role in the pathogenesis of CRSwNP. PRDX2 modulates ROS-induced epithelial remodeling, contributing to disease progression by activating the TGF-β1/Smad signaling pathway.
FokkensWJLundVJHopkinsC, et al.European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(Suppl S29):1–464. DOI: 10.4193/Rhin20.600
2.
ChoSHHamilosDLHanDH, et al.Phenotypes of chronic rhinosinusitis. J Allergy Clin Immunol Pract. 2020;8(5):1505–1511. DOI: 10.1016/j.jaip.2019.12.021
3.
JoSLeeSHJoHR, et al.Eosinophil-derived TGFβ1 controls the new bone formation in chronic rhinosinusitis with nasal polyps. Rhinology. 2023;61(4):338–347. DOI: 10.4193/Rhin22.439
4.
XieSTongZZhangJ, et al.Elevated MIF identified by multiple cytokine analyses facilitates macrophage M2 polarization contributing to postoperative recurrence in chronic rhinosinusitis with nasal polyps. Rhinology. 2024;62(4):432–445. DOI: 10.4193/Rhin23.412
5.
ZhouJZhouJLiuRW, et al.The oxidant-antioxidant imbalance was involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. Front Immunol. 2024;15:1380846.
6.
LiuCWangKLiuW, et al.ALOX15(+) M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2024;154(3):592–608. DOI: 10.1016/j.jaci.2024.04.019
7.
LiPWangWZhuB, et al.PRDX2 regulates stemness contributing to cisplatin resistance and metastasis in bladder cancer. Environ Toxicol. 2024;39(5):2869–2880. DOI: 10.1002/tox.24153
8.
DongYHanFSuY, et al.High uric acid aggravates apoptosis of lung epithelial cells induced by cigarette smoke extract through downregulating PRDX2 in chronic obstructive pulmonary disease. Int Immunopharmacol. 2023;118:110056. DOI: 10.1016/j.intimp.2023.110056
9.
KwonHSBaeYJMoonKA, et al.Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity. Life Sci. 2012;90(13–14):502–508. DOI: 10.1016/j.lfs.2012.01.003
10.
FengJFuZGuoJ, et al.Overexpression of peroxiredoxin 2 inhibits TGF-beta1-induced epithelial-mesenchymal transition and cell migration in colorectal cancer. Mol Med Rep. 2014;10(2):867–873. DOI: 10.3892/mmr.2014.2316
11.
LiuFSuHLiuB, et al.STVNa attenuates isoproterenol-induced cardiac hypertrophy response through the HDAC4 and Prdx2/ROS/Trx1 pathways. Int J Mol Sci.2020; 21(2):682. DOI: 10.3390/ijms21020682
12.
WangWXuYWangL, et al.Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis. Nat Immunol.2022;23(10):1484–1494. DOI: 10.1038/s41590-022-01312-0
13.
LiuCWangKLiuW, et al.ALOX15(+) M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2024;154(3):592–608. DOI: 10.1016/j.jaci.2024.04.019
14.
ChenYGaoRLiuH, et al.Serum proteomic analysis revealed biomarkers for eosinophilic chronic rhinosinusitis with nasal polyps pathophysiology. J Inflamm Res.2024;17:805–821. DOI: 10.2147/jir.S444280
15.
GaoRChenYLiuH, et al.CD109 identified in circulating proteomics mitigates postoperative recurrence in chronic rhinosinusitis with nasal polyps by suppressing TGF-β1-induced epithelial-mesenchymal transition. Int Immunopharmacol. 2024;130:111793. DOI: 10.1016/j.intimp.2024.111793
16.
LiLYZhouYTSunL, et al.Downregulation of MCM2 contributes to the reduced growth potential of epithelial progenitor cells in chronic nasal inflammation. J Allergy Clin Immunol. 2021;147(5):1966–1973, e1963. DOI: 10.1016/j.jaci.2020.11.026
17.
FanCYangYYouM, et al.Mefunidone inhibits inflammation, oxidative stress, and epithelial-mesenchymal transition in lens epithelial cells. Invest Ophthalmol Vis Sci. 2024;65(14):17. DOI: 10.1167/iovs.65.14.17
18.
JoachimJMaselliDPetsolariE, et al.TNIK: A redox sensor in endothelial cell permeability. Sci Adv.2024;10(51):eadk6583. DOI: 10.1126/sciadv.adk6583
19.
Ghafouri-FardSAskariAShooreiH, et al.Antioxidant therapy against TGF-β/SMAD pathway involved in organ fibrosis. J Cell Mol Med.2024;28(2):e18052. DOI: 10.1111/jcmm.18052
20.
TsaiYJHsuYTMaMC, et al.Transcriptomic analysis of genes associated with oxidative stress in chronic rhinosinusitis patients with nasal polyps: Identifying novel genes involved in nasal polyposis. Antioxidants (Basel, Switzerland). 2022;11(10):1899. DOI: 10.3390/antiox11101899
21.
BiedrzyckiGWolszczak-BiedrzyckaBDorfJ, et al.The antioxidant barrier, oxidative/nitrosative stress, and protein glycation in allergy: From basic research to clinical practice. Front Immunol. 2024;15:1440313. DOI: 10.3389/fimmu.2024.1440313
22.
HuangGXMandanasMVDjeddiS, et al.Increased glycolysis and cellular crosstalk in eosinophilic chronic rhinosinusitis with nasal polyps. Front Immunol. 2024;15:1321560. DOI: 10.3389/fimmu.2024.1321560
23.
JiangSZhangBWenS, et al.NOX2 mediates NLRP3/ROS facilitating nasal mucosal epithelial inflammation in chronic rhinosinusitis with nasal polyps. Heliyon. 2024;10(18):e38029. DOI: 10.1016/j.heliyon.2024.e38029
24.
ZhangZWangYLiuY, et al.Involvement of the PRDX family and its clinical functions in different types of gastrointestinal cancer (Review). Oncol Rep. 2025;54(2):90. DOI: 10.3892/or.2025.8923
25.
QiuTAziziSAPaniS, et al.Dynamic PRDX S-acylation modulates ROS stress and signaling. Cell Chem Biol. 2025;32(3):511–519 e515. DOI: 10.1016/j.chembiol.2025.01.009
26.
O'FlahertyC. Redox signaling regulation in human spermatozoa: a primary role of peroxiredoxins. Asian J Androl. 2025;27(5):556–563. DOI: 10.4103/aja2024126
27.
ChenQThompsonJHuY, et al.Endoplasmic reticulum stress and alterations of peroxiredoxins in aged hearts. Mech Ageing Dev. 2023;215:111859. DOI: 10.1016/j.mad.2023.111859
28.
BalasubramanianPVijayarangamVDeviparasakthiMKG, et al.Implications and progression of peroxiredoxin 2 (PRDX2) in various human diseases. Pathol Res Pract. 2024;254:155080. DOI: 10.1016/j.prp.2023.155080
29.
LiJWangCWangW, et al.PRDX2 protects against atherosclerosis by regulating the phenotype and function of the vascular smooth muscle cell. Front Cardiovasc Med. 2021;8:624796. DOI: 10.3389/fcvm.2021.624796
30.
MihaljHButkovicJTokicS, et al.Expression of oxidative stress and inflammation-related genes in nasal mucosa and nasal polyps from patients with chronic rhinosinusitis. Int J Mol Sci.2022; 23(10):5521. DOI: 10.3390/ijms23105521
31.
VoigtDScheidtUDerfussT, et al.Expression of the antioxidative enzyme peroxiredoxin 2 in multiple sclerosis lesions in relation to inflammation. Int J Mol Sci. 2017;18(4):760. DOI: 10.3390/ijms18040760
32.
RuanJTianQLiS, et al.The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial-mesenchymal transition by phosphorylating beta-catenin. Cell Commun Signal. 2024;22(1):318. DOI: 10.1186/s12964-024-01683-x
33.
ShiJZhouLHuangHS, et al.Repurposing oxiconazole against colorectal cancer via PRDX2-mediated autophagy arrest. Int J Biol Sci. 2022;18(9):3747–3761. DOI: 10.7150/ijbs.70679
34.
NomaIHYCarvalhoLCamarenaDEM, et al.Peroxiredoxin-2 represses NRAS-mutated melanoma cells invasion by modulating EMT markers. Biomed Pharmacother.2024;177:116953. DOI: 10.1016/j.biopha.2024.116953
35.
SunHNRenCXLeeDH, et al.PRDX1 negatively regulates bleomycin-induced pulmonary fibrosis via inhibiting the epithelial-mesenchymal transition and lung fibroblast proliferation in vitro and in vivo. Cell Mol Biol Lett.2023;28(1):48. DOI: 10.1186/s11658-023-00460-x
36.
ZhouJChengAGuoJ, et al.Targeting PRDX2 to inhibit tumor growth and metastasis in triple-negative breast cancer: The role of FN1 and the PI3K/AKT/SP1 pathway. J Transl Med.2025;23(1):434. DOI: 10.1186/s12967-025-06441-2
37.
ChandimaliNHuynhDLZhangJJ, et al.MicroRNA-122 negatively associates with peroxiredoxin-II expression in human gefitinib-resistant lung cancer stem cells. Cancer Gene Ther.2019;26(9–10):292–304. DOI: 10.1038/s41417-018-0050-1
38.
AhnHMYooJWLeeS, et al.Peroxiredoxin 5 promotes the epithelial-mesenchymal transition in colon cancer. Biochem Biophys Res Commun.2017;487(3):580–586. DOI: 10.1016/j.bbrc.2017.04.094
39.
ChaeUKimBKimH, et al.Peroxiredoxin-6 regulates p38-mediated epithelial-mesenchymal transition in HCT116 colon cancer cells. J Biol Res (Thessalonike, Greece). 2021;28(1):22. DOI: 10.1186/s40709-021-00153-6
40.
ChenMWuGBHuaS, et al.Dibutyl phthalate (DBP) promotes epithelial-mesenchymal transition (EMT) to aggravate liver fibrosis into cirrhosis and portal hypertension (PHT) via ROS/TGF-beta1/snail-1 signalling pathway in adult rats. Ecotoxicol Environ Saf. 2024;274:116124. DOI: 10.1016/j.ecoenv.2024.116124
41.
ZhuYYinWFYuP, et al.Meso-Hannokinol inhibits breast cancer bone metastasis via the ROS/JNK/ZEB1 axis. Phytother Res. 2023;37(6):2262–2279. DOI: 10.1002/ptr.7732
42.
LiJZouYKantapanJ, et al.TGF-beta/Smad signaling in chronic kidney disease: Exploring post-translational regulatory perspectives (Review). Mol Med Rep. 2024;30(2):143. DOI: 10.3892/mmr.2024.13267
43.
YaoZFuY. Glycyrrhizic acid restrains airway inflammation and remodeling in asthma via the TGF-beta1/Smad signaling pathway. Exp Ther Med. 2021;21(5):461. DOI: 10.3892/etm.2021.9892
44.
XueCLinXPZhangJM, et al.Beta-Elemene suppresses the proliferation of human airway granulation fibroblasts via attenuation of TGF-beta/Smad signaling pathway. J Cell Biochem. 2019;120(10):16553–16566. DOI: 10.1002/jcb.28915
45.
ZengRZhangDZhangJ, et al.Targeting lysyl oxidase like 2 attenuates OVA-induced airway remodeling partly via the AKT signaling pathway. Respir Res. 2024;25(1):230. DOI: 10.1186/s12931-024-02811-4
46.
HuangSZhouRYuanY, et al.Stigmasterol alleviates airway inflammation in OVA-induced asthmatic mice via inhibiting the TGF-beta1/Smad2 and IL-17A signaling pathways. Aging (Albany NY). 2024;16(7):6478–6487. DOI: 10.18632/aging.205716
47.
LiZChengTGuoY, et al.CD147 induces asthmatic airway remodeling and activation of circulating fibrocytes in a mouse model of asthma. Respir Res. 2024;25(1):6. DOI: 10.1186/s12931-023-02646-5
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