{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:15Z","timestamp":1785428115295,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research through the \u201cProjects of great national interest\u201d (PRIN) 2022","award":["20223H8LFM_001"],"award-info":[{"award-number":["20223H8LFM_001"]}]},{"name":"Italian Ministry of Economic Development\u2014MISE \u201cInCube\u201d","award":["F\/200035\/02\/X45"],"award-info":[{"award-number":["F\/200035\/02\/X45"]}]},{"award":["F\/200035\/02\/X45"],"award-info":[{"award-number":["F\/200035\/02\/X45"]}],"id":[{"id":"https:\/\/ror.org\/011z3ff80","id-type":"ROR","asserted-by":"publisher"}]},{"name":"PhD program in Molecular Life Sciences from University of Campania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Leydig cells (LCs) represent a somatic testicular population responsible for testosterone synthesis, a hormone essential for spermatogenesis and male fertility. The obesity condition impairs LC steroidogenic activity, contributing to testicular oxidative stress and male reproductive dysfunctions. Using a high-fat-diet (HFD) murine model, we investigated the regulatory role of the nuclear factor of activated T cells 5 (NFAT5s) in the obesity-induced LC damage and the resulting alterations in intergenerationally inherited sperm circRNA cargo. Our findings reveal a significant upregulation of both circNFAT5 and NFAT5 protein levels in HFD testis. This molecular signature correlated with decreased antioxidant defense system, increased LC apoptosis, and impaired steroidogenesis. In vitro experiments, performed in TM3 cells, confirmed that NFAT5 nuclear shuttling drives proapoptotic gene activation, while NFAT5 silencing promotes LC survival. The analysis of HFD progeny (F1H) revealed a full recovery of testis oxidative status and LC apoptosis, linked with the recovery of NFAT5 expression. However, a steroidogenic deficiency persisted in F1H offspring. Notably, HFD and F1H epididymides exhibited NFAT5 overexpression concomitantly with impaired sperm morphology, motility, viability, and altered sperm circRNA profiles alongside a deregulated 4-hydroxy-2-nonenal (4HNE) profile, a marker of sperm oxidative stress. Lastly, an enhanced FUS-related amplification of circRNA perturbations was highlighted in F1H spermatozoa. Collectively, our findings reveal a dual functional role of NFAT5 as a testicular regulator of LC fate and an epididymal sentinel of metabolic stress, in turn linking paternal obesity to the persistent transmission of sperm epigenetic anomalies across the offspring.<\/jats:p>","DOI":"10.3390\/antiox15050645","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:02:27Z","timestamp":1779375747000},"page":"645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NFAT5: A Metabolic Time Capsule Encoding the History of Paternal Metabolic Oxidative Stress Within the Male Reproductive Tract"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0405-3807","authenticated-orcid":false,"given":"Nicola","family":"Mosca","sequence":"first","affiliation":[{"name":"Department of Environmental, Biological, Pharmaceutical Sciences and Technologies, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Migliaccio","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1720-1496","authenticated-orcid":false,"given":"Teresa","family":"Chioccarelli","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donato","family":"Cappetta","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marialucia","family":"Telesca","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5173-363X","authenticated-orcid":false,"given":"Liberato","family":"Berrino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3984-3784","authenticated-orcid":false,"given":"Danila","family":"Valletta","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological, Pharmaceutical Sciences and Technologies, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4946-7336","authenticated-orcid":false,"given":"Alice","family":"Luddi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Development, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2224-4199","authenticated-orcid":false,"given":"Chiara","family":"Donati","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, 50100 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2987-7028","authenticated-orcid":false,"given":"Paola","family":"Piomboni","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Development, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-8098","authenticated-orcid":false,"given":"Charles","family":"Coutton","sequence":"additional","affiliation":[{"name":"H\u00f4pital Couple-Enfant, Centre Hospitalier Universitaire de Grenoble, UM de G\u00e9n\u00e9tique Chromosomique, 38000 Grenoble, France"},{"name":"Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences INSERM U1209, CNRS UMR5309, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-9096","authenticated-orcid":false,"given":"Guillaume","family":"Martinez","sequence":"additional","affiliation":[{"name":"H\u00f4pital Couple-Enfant, Centre Hospitalier Universitaire de Grenoble, UM de G\u00e9n\u00e9tique Chromosomique, 38000 Grenoble, France"},{"name":"Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences INSERM U1209, CNRS UMR5309, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5884-9208","authenticated-orcid":false,"given":"Gilda","family":"Cobellis","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1066-843X","authenticated-orcid":false,"given":"Chiara","family":"Schiraldi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9736-792X","authenticated-orcid":false,"given":"Nicoletta","family":"Potenza","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological, Pharmaceutical Sciences and Technologies, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3631-1794","authenticated-orcid":false,"given":"Rosanna","family":"Chianese","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania 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