NEDD4 Knockdown Suppresses Human Endometrial Stromal Cell Growth and Invasion by Regulating PTGS2-Mediated Ferroptosis in Endometriosis

Jianting Lao, Panwei Hu, Yiting Wan, Mengmeng Shu, Jing Chen, Hong Yang
Current molecular medicine · 2025 · vol. 25(9) , pp. 1154–1166 · doi:10.2174/0115665240311438241011052341 · PMID:39501947
other OA: closed public-domain-us
Full text JSON View on PubMed View at publisher
⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

NEDD4 knockdown suppressed human endometrial stromal cell growth and invasion by increasing PTGS2-mediated ferroptosis, as NEDD4 targets PTGS2 for ubiquitination and degradation.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

The paper investigates whether abnormal expression of NEDD4 is associated with endometriosis and evaluates NEDD4’s effects on human endometrial stromal cell (ESC) growth and invasion. Using endometrial tissue from patients without endometriosis to generate ESCs, and patient endometriosis ectopic versus eutopic tissues for NEDD4 assessment by immunohistochemistry and western blotting, the study finds significantly elevated NEDD4 in endometriosis, with higher levels in ectopic than eutopic endometrium. Functionally, NEDD4 knockdown reduced ESC viability and invasion in vitro (cell counting, FDA staining, Transwell assays), increased ferroptosis-associated markers (Fe2+, MDA, ROS) while decreasing GSH, and promoted ferroptosis via upregulation of PTGS2; mechanistically, NEDD4 reduced PTGS2 protein by accelerating ubiquitination and proteasomal degradation. This paper uses primarily in vitro ESC experiments and does not provide an explicit limitation in the abstract regarding model generalizability, which is a caveat for translation. This paper is centrally about endometriosis — it shows NEDD4 is elevated in endometriosis tissues and that NEDD4 knockdown suppresses ESC growth and invasion through PTGS2-dependent ferroptosis.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Abstract

BACKGROUND: Endometriosis (EM) is a gynecological disease characterized by the benign growth of endometrial tissue outside the uterus. Upregulation of neuronally expressed developmentally downregulated 4 (NEDD4) has been reported to accelerate endometrial cancer progression. OBJECTIVES: We explored whether abnormal expression of NEDD4 is correlated with EM. METHODS: Endometrial tissue in patients without endometriosis was used to develop the original generation of endometrial stromal cells (ESCs). Different types of endometrial tissue of patients with endometriosis were used to measure the expression of NEDD4 by immunohistochemistry (IHC) and western blotting. Its biological functions in ESCs were investigated using a cell counting kit-8 assay, fluorescein diacetate (FDA) staining, and Transwell invasion assays. Additionally, its involvement in ferroptosis was assessed by measuring Fe2+, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels and the expression of ferroptosis markers. RESULTS: Compared with normal controls, NEDD4 levels were significantly elevated in the endometrial tissue of patients with EM. Furthermore, NEDD4 expression was higher in the ectopic endometrium than in the eutopic endometrium. NEDD4 knockdown reduced the viability and invasive capacity of ESCs, increased Fe2+, MDA, and ROS levels, and decreased GSH content. Further analysis revealed that NEDD4 knockdown promoted ferroptosis in ESCs by increasing the expression of prostaglandin-endoperoxide synthase 2 (PTGS2). As an E3 ubiquitin ligase, NEDD4 reduced PTGS2 protein levels by accelerating its ubiquitination and subsequent proteasomal degradation. CONCLUSION: These findings suggest that inhibiting NEDD4 reduces ESC growth and invasion in EM by regulating PTGS2-dependent ferroptosis.
Full text 6,694 characters · extracted from oa-doi-fallback · 6 sections · click to expand

Abstract

Background: Endometriosis (EM) is a gynecological disease characterized by the benign growth of endometrial tissue outside the uterus. Upregulation of neuronally expressed developmentally downregulated 4 (NEDD4) has been reported to accelerate endometrial cancer progression.

Objectives

We explored whether abnormal expression of NEDD4 is correlated with EM.

Methods

Endometrial tissue in patients without endometriosis was used to develop the original generation of endometrial stromal cells (ESCs). Different types of endometrial tissue of patients with endometriosis were used to measure the expression of NEDD4 by immunohistochemistry (IHC) and western blotting. Its biological functions in ESCs were investigated using a cell counting kit-8 assay, fluorescein diacetate (FDA) staining, and Transwell invasion assays. Additionally, its involvement in ferroptosis was assessed by measuring Fe2+, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels and the expression of ferroptosis markers.

Results

Compared with normal controls, NEDD4 levels were significantly elevated in the endometrial tissue of patients with EM. Furthermore, NEDD4 expression was higher in the ectopic endometrium than in the eutopic endometrium. NEDD4 knockdown reduced the viability and invasive capacity of ESCs, increased Fe2+, MDA, and ROS levels, and decreased GSH content. Further analysis revealed that NEDD4 knockdown promoted ferroptosis in ESCs by increasing the expression of prostaglandin-endoperoxide synthase 2 (PTGS2). As an E3 ubiquitin ligase, NEDD4 reduced PTGS2 protein levels by accelerating its ubiquitination and subsequent proteasomal degradation.

Conclusion

These findings suggest that inhibiting NEDD4 reduces ESC growth and invasion in EM by regulating PTGS2-dependent ferroptosis.

Keywords

NEDD4, PTGS2, endometriosis, ferroptosis, endometrial stromal cells, cell viability. [http://dx.doi.org/10.3389/frph.2021.729642] [PMID: 36303969] [http://dx.doi.org/10.1038/s41574-019-0245-z] [PMID: 31488888] [http://dx.doi.org/10.1186/s12967-020-02471-0] [PMID: 32787880] [http://dx.doi.org/10.1136/bmj-2022-070750] [PMID: 36375827] [http://dx.doi.org/10.1016/S0140-6736(21)00389-5] [PMID: 33640070] [http://dx.doi.org/10.1007/s00404-020-05586-3] [PMID: 32430756] [http://dx.doi.org/10.1007/s00404-021-06129-0] [PMID: 34148122] [http://dx.doi.org/10.3389/fmed.2022.879015] [PMID: 35572957] [http://dx.doi.org/10.1146/annurev-pathmechdis-012419-032654] [PMID: 31479615] [http://dx.doi.org/10.1016/S0002-9378(15)30003-X] [http://dx.doi.org/10.1136/bmj-2021-068950] [PMID: 36442873] [http://dx.doi.org/10.1016/S0015-0282(02)03346-0] [PMID: 12372445] [http://dx.doi.org/10.3390/ijms24021619] [PMID: 36675136] [http://dx.doi.org/10.1016/j.tox.2021.153050] [PMID: 34826546] [http://dx.doi.org/10.3390/biomedicines8110454] [PMID: 33121166] [http://dx.doi.org/10.1186/s12943-022-01530-y] [PMID: 35151318] [http://dx.doi.org/10.1016/j.redox.2017.01.021] [PMID: 28212525] [http://dx.doi.org/10.1038/s41580-020-00324-8] [PMID: 33495651] [http://dx.doi.org/10.1007/s00011-022-01672-1] [PMID: 36536250] [http://dx.doi.org/10.1016/j.ejcb.2019.151058] [PMID: 31810634] [http://dx.doi.org/10.1111/cpr.12761] [PMID: 32100402] [http://dx.doi.org/10.3390/cells8020198] [PMID: 30813496] [http://dx.doi.org/10.1038/s41598-022-04963-z] [PMID: 35173188] [http://dx.doi.org/10.1038/s41580-023-00648-1] [PMID: 37783783] [http://dx.doi.org/10.1155/2017/7265238] [PMID: 29057034] [http://dx.doi.org/10.1007/s43032-020-00164-z] [PMID: 32077077] [http://dx.doi.org/10.1038/d41586-021-01203-8] [PMID: 33981062] [http://dx.doi.org/10.1016/j.biopha.2018.06.109] [PMID: 29958140] [http://dx.doi.org/10.3389/fphys.2021.702674] [PMID: 34712146] [http://dx.doi.org/10.1016/j.biopha.2020.109983] [PMID: 32092816] [http://dx.doi.org/10.7150/ijbs.48437] [PMID: 33110392] [http://dx.doi.org/10.3390/ijms23073882] [PMID: 35409239] [http://dx.doi.org/10.1016/j.semcancer.2020.03.006] [PMID: 32171886] [http://dx.doi.org/10.1038/s41467-020-14324-x] [PMID: 31974380] [http://dx.doi.org/10.1016/j.jdermsci.2023.09.007] [PMID: 37932175] [http://dx.doi.org/10.1111/cns.14685] [PMID: 38634270] [http://dx.doi.org/10.1016/j.bbrc.2020.07.032] [PMID: 32811647] [http://dx.doi.org/10.1186/s13058-019-1236-7] [PMID: 31856858] [http://dx.doi.org/10.1016/j.ygyno.2015.07.098] [PMID: 26193427] [http://dx.doi.org/10.3892/mmr.2021.11995] [PMID: 33760149] [http://dx.doi.org/10.1093/humrep/dei414] [PMID: 16517565] [http://dx.doi.org/10.1016/j.cell.2006.11.039] [PMID: 17218260] [http://dx.doi.org/10.1093/humrep/deh571] [PMID: 15579491] [http://dx.doi.org/10.1016/j.phymed.2023.155187] [PMID: 37984125] [http://dx.doi.org/10.1186/s12964-024-01683-x] [PMID: 38858740] [http://dx.doi.org/10.1177/1933719113488449] [PMID: 23653392] [http://dx.doi.org/10.1016/j.fertnstert.2020.05.005] [PMID: 32762950] [http://dx.doi.org/10.1016/j.tiv.2015.08.010] [PMID: 26318276] [http://dx.doi.org/10.1186/s11658-022-00383-z] [PMID: 36180832] [http://dx.doi.org/10.1016/j.vascn.2018.03.007] [PMID: 29630935] [http://dx.doi.org/10.1007/s00018-013-1333-1] [PMID: 23579629] [http://dx.doi.org/10.1007/s10540-005-2847-z] [PMID: 16222419] [http://dx.doi.org/10.1111/all.12810] [PMID: 26606373] [http://dx.doi.org/10.3390/ijms22179274] [PMID: 34502183] [http://dx.doi.org/10.1093/humrep/deaa363] [PMID: 33378529] [http://dx.doi.org/10.1038/s41420-022-00821-z] [PMID: 35039492] [http://dx.doi.org/10.1186/s12929-021-00731-9] [PMID: 33962630] [http://dx.doi.org/10.1016/j.fertnstert.2012.06.029] [PMID: 22819144] [http://dx.doi.org/10.1016/S0140-6736(05)67063-8] [PMID: 16084259] [http://dx.doi.org/10.3389/fmolb.2022.929832] [PMID: 35847989] [PMID: 19969738] [http://dx.doi.org/10.1007/978-3-319-18308-4_5] [http://dx.doi.org/10.1016/j.fertnstert.2008.02.103] [PMID: 18396284] [http://dx.doi.org/10.3109/00016349209021069] [PMID: 1326207] [http://dx.doi.org/10.3390/biom12111702] [PMID: 36421722] [http://dx.doi.org/10.1093/hropen/hoad033] [PMID: 37638130] [http://dx.doi.org/10.1016/j.rbmo.2021.04.002] [PMID: 33992553] [http://dx.doi.org/10.1093/molehr/gaad046] [PMID: 38113413] [http://dx.doi.org/10.3389/fimmu.2021.671201] [PMID: 34539624] [http://dx.doi.org/10.3389/fonc.2021.774648] [PMID: 34869021] [http://dx.doi.org/10.3389/fphar.2023.1291773] [PMID: 38027016] [http://dx.doi.org/10.3390/ijms22179182] [PMID: 34502089] [http://dx.doi.org/10.4161/cc.26672] [PMID: 24107629] [http://dx.doi.org/10.1016/j.bioorg.2021.104744] [PMID: 33639365] [http://dx.doi.org/10.3389/fcell.2021.672335] [PMID: 34222246] [http://dx.doi.org/10.1038/cdd.2009.84] [PMID: 19557014] [http://dx.doi.org/10.1016/j.psyneuen.2014.06.015] [PMID: 25058273]

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: oa-doi-fallback ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

endometriosis

MeSH descriptors

Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2

Citation neighborhood (no data yet)

We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2025) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.

Source provenance

europepmc
last seen: 2026-07-27T06:15:28.040536+00:00
pubmed
last seen: 2026-07-27T06:12:28.573690+00:00
unpaywall
last seen: 2026-05-11T08:34:28.763810+00:00
License: public-domain-us · commercial use OK · attribution required
Courtesy of the U.S. National Library of Medicine