Ubiquitination of PFKFB4 by CHIP regulates glycolysis and progression in endometriosis

Yujie Tang, Ran Wei, Runze Zhao, Lu Liu, Xuemei Zhang, Zhenhai Yu, Chao Lü
Biology of reproduction · 2025 · vol. 113(3) , pp. 568–580 · doi:10.1093/biolre/ioaf159 · PMID:40684802 · W4412555131
article OA: closed CC0
View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

The E3 ubiquitin ligase CHIP ubiquitinates and degrades the key glycolytic enzyme PFKFB4, suppressing its activity and thereby regulating endometriosis progression.

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

Abstract

Endometriosis is a common estrogen-dependent gynecological disorder characterized by chronic inflammatory responses and frequently associated with clinical infertility. Recent studies have demonstrated that the pathogenesis of this disease is closely linked to dysregulated post-translational modifications. This study focuses on the regulatory role of the ubiquitin-proteasome system (UPS) in endometriosis and, for the first time, reveals the molecular mechanism by which the E3 ubiquitin ligase STIP1 homology and U-box containing protein 1 (CHIP) specifically binds to and ubiquitinates the glycolytic key enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), thereby promoting its degradation and modulating endometriosis progression. Notably, PFKFB4 is aberrantly overexpressed in ectopic endometrial tissues, with its lysine 305 (K305) residue identified as the critical ubiquitination site mediated by CHIP. Functional studies demonstrate that CHIP-mediated ubiquitination of PFKFB4 significantly suppresses glycolytic activity and inhibits the invasive and migratory capacities of endometriotic cells. More importantly, we provide the first evidence that the PFKFB4 inhibitor 5-(n-(8-methoxy-4-quinolyl) amino) pentyl nitrate (5MPN) exerts potent therapeutic effects in both in vitro and in vivo experimental models of endometriosis. In summary, this study elucidates the crucial regulatory role of CHIP-mediated PFKFB4 ubiquitination in the metabolic reprogramming of endometriosis while also identifying a novel molecular target for developing ubiquitination-targeted therapeutic strategies.

My notes (saved in your browser only)

Condition tags

mesh:D004715endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

Funding

funders
[{'doi': None, 'name': 'Graduate Student Research Grant from Shandong Second Medical University', 'awards': ['2024YJSCX012']}, {'doi': None, 'name': 'Graduate Student Research Grant from Shandong Second Medical University', 'awards': ['2023YJSCX014']}, {'doi': None, 'name': 'National Natural Science Foundation of Shandong Province', 'awards': ['ZR2024QH019']}, {'doi': None, 'name': 'Foundation of Weifang Kite Capital Scholars', 'awards': ['ydxz2023021']}, {'doi': '10.13039/501100018627', 'name': 'Science and Technology Support Plan for Youth Innovation of Colleges and Universities of Shandong Province of China', 'awards': ['2021KJ107']}]

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (96)

Source provenance

crossref
last seen: 2026-05-16T01:00:05.935713+00:00
europepmc
last seen: 2026-06-04T01:30:01.192114+00:00
openalex
last seen: 2026-06-10T17:14:06.276822+00:00
pubmed
last seen: 2026-05-29T00:31:10.604959+00:00
unpaywall
last seen: 2026-06-02T02:00:03.124865+00:00
License: CC0 · commercial use OK