{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:57:24Z","timestamp":1760144244051,"version":"build-2065373602"},"reference-count":112,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan, ROC","award":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"],"award-info":[{"award-number":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"]}]},{"name":"National Health Research Institute","award":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"],"award-info":[{"award-number":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"]}]},{"name":"Department of Defense USA","award":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"],"award-info":[{"award-number":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We reported that a 31-amino-acid Zfra protein (zinc finger-like protein that regulates apoptosis) blocks neurodegeneration and cancer growth. Zfra binds WW domain-containing oxidoreductase (WWOX) to both N- and C-termini, which leads to accelerated WWOX degradation. WWOX limits the progression of neurodegeneration such as Alzheimer\u2019s disease (AD) by binding tau and tau-hyperphosphorylating enzymes. Similarly, Zfra binds many protein targets and accelerates their degradation independently of ubiquitination. Furthermore, Zfra4-10 peptide strongly prevents the progression of AD-like symptoms in triple-transgenic (3xTg) mice during aging. Zfra4-10 peptide restores memory loss in 9-month-old 3xTg mice by blocking the aggregation of a protein cascade, including TPC6A\u0394, TIAF1, and SH3GLB2, by causing aggregation of tau and amyloid \u03b2. Zfra4-10 also suppresses inflammatory NF-\u03baB activation. Zfra-activated Hyal-2+ CD3- CD19- Z cells in the spleen, via Hyal-2\/WWOX\/Smad4 signaling, are potent in cancer suppression. In this perspective review, we provide mechanistic insights regarding how Zfra overrides WWOX to induce cancer suppression and retard AD progression via Z cells.<\/jats:p>","DOI":"10.3390\/ijms25063507","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T09:14:33Z","timestamp":1710926073000},"page":"3507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration"],"prefix":"10.3390","volume":"25","author":[{"given":"Yu-An","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsung-Yun","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuan-Yu","family":"Wen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Che-Yu","family":"Hsu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-I","family":"Sze","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6889-8756","authenticated-orcid":false,"given":"Nan-Shan","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, New York, NY 10314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41573-019-0016-5","article-title":"Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond","volume":"18","author":"Platten","year":"2019","journal-title":"Nat. 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