{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T10:29:53Z","timestamp":1786616993310,"version":"build-2736575974"},"reference-count":85,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007471","name":"Northern Border University","doi-asserted-by":"publisher","award":["NBU-CRP-2026-1442"],"award-info":[{"award-number":["NBU-CRP-2026-1442"]}],"id":[{"id":"10.13039\/501100007471","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NBU-CRP-2026-1442"],"award-info":[{"award-number":["NBU-CRP-2026-1442"]}],"id":[{"id":"https:\/\/ror.org\/03j9tzj20","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Cisplatin is a widely used chemotherapeutic agent whose gonadotoxic effects, largely driven by oxidative stress and inflammation, pose a major threat to male reproductive health. This study evaluated whether hesperetin (HES) and hesperetin-loaded poly (lactic-co-glycolic acid) nanoparticles (HES-PLGA-NPs) can protect against cisplatin-induced testicular dysfunction in adult male Sprague Dawley rats. Methods: Sixty rats were randomly assigned to six groups: control, HES, HES-PLGA-NPs, cisplatin (CIS), CIS + HES, and CIS + HES-PLGA-NPs. CIS (7.5 mg\/kg\/week, i.p.) was given intraperitoneally for four weeks, while HES and nano-HES (50 mg\/kg\/day, p.o.) were orally administered concurrently. Reproductive hormones, testicular weight, sperm parameters, oxidative stress and antioxidant markers, NRF2\/HO-1 and NF-\u03baB signaling, apoptotic indices, ferroptosis-related markers, histopathology, and GPX4\/ACSL4 immunoexpression were assessed. Results: CIS caused marked reproductive dysfunction, including reduced testosterone, FSH, and LH, decreased testicular weight, and impaired sperm quality. These changes were associated with severe oxidative and nitrosative stress (\u2191 MDA, NO, 8-OHdG), depletion of antioxidant defenses (\u2193 SOD, CAT, GSH), reduced NRF2\/HO-1, elevated NF-\u03baB activity and pro-inflammatory cytokines, apoptosis-related changes (\u2191 Bax, caspase-3; \u2193 Bcl-2), and ferroptosis-associated alterations (\u2191 Fe2+, TFR1, lipid ROS, ACSL4, 4-HNE; \u2193 GPX4, SLC7A11). Both HES and HES-PLGA-NPs were associated with significant amelioration of these alterations, but the nanoformulation showed more pronounced protection, normalizing several oxidative and ferroptosis-associated markers toward control levels and more effectively preserving seminiferous tubule architecture and spermatogenesis. Conclusions: HES-PLGA-NPs were associated with multi-mechanistic protection against cisplatin-induced oxidative, inflammatory, apoptotic, and ferroptosis-associated damage in the testes, and may represent a promising nanoantioxidant candidate warranting further investigation for preserving male reproductive function during chemotherapy.<\/jats:p>","DOI":"10.3390\/antiox15081007","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:31:09Z","timestamp":1786613469000},"page":"1007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hesperetin-Loaded PLGA Nanoparticles Ameliorate Cisplatin-Induced Oxidative Stress and Testicular Dysfunction in Rats: Association with NRF2\/HO-1, NF-\u03baB, and ACSL4\/GPX4\/SLC7A11 Signaling Modulation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2573-9309","authenticated-orcid":false,"given":"Mohammed A.","family":"Akeel","sequence":"first","affiliation":[{"name":"Department of Human Anatomy, Faculty of Medicine, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7444-2499","authenticated-orcid":false,"given":"Ekramy M.","family":"Elmorsy","sequence":"additional","affiliation":[{"name":"Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1908-4788","authenticated-orcid":false,"given":"Aly A. M.","family":"Shaalan","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Faculty of Medicine, Jazan University, Jazan 45142, Saudi Arabia"},{"name":"Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6160-5284","authenticated-orcid":false,"given":"Fahad","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5540-0819","authenticated-orcid":false,"given":"Ezzat A.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2924-9670","authenticated-orcid":false,"given":"Gehad E.","family":"Elshopakey","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1252-8403","authenticated-orcid":false,"given":"Manal S.","family":"Fawzy","sequence":"additional","affiliation":[{"name":"Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2810-3613","authenticated-orcid":false,"given":"Shaimaa A.","family":"Shehata","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106939","DOI":"10.1016\/j.ejps.2024.106939","article-title":"Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies","volume":"203","author":"Elmorsy","year":"2024","journal-title":"Eur. 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