{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:33:16Z","timestamp":1787585596139,"version":"build-2736575974"},"reference-count":76,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"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":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Manganese (Mn) is a neurotoxic trace element whose excessive accumulation in the brain can induce hippocampal damage via oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. This study investigated whether honokiol (HNK) and its liposomal nanoformulation (HNK-LNPs) can ameliorate Mn-induced hippocampal neurotoxicity by modulating key antioxidant and mitochondrial regulatory pathways. Methods: Male Wistar rats were subjected to Mn exposure to induce hippocampal neurotoxicity and were treated with HNK or HNK-LNPs. We assessed oxidative status via NRF2\/HO-1 signaling, antioxidant defenses (glutathione, GPx, SOD, CAT), and oxidative indices (ROS, MDA). Neuroinflammatory markers (NF-\u03baB, TNF-\u03b1, IL-1\u03b2, IL-6, Iba-1), mitochondrial respiratory chain function and ATP levels, SIRT1\/PGC-1\u03b1 signaling, and neurotransmitter homeostasis were evaluated. We analyzed apoptosis using Bax, Bcl-2, caspase-3, and cytochrome c, along with histopathological and ultrastructural examination of the hippocampus. Results: Mn exposure was associated with NRF2\/HO-1 downregulation, depleted endogenous antioxidants, increased ROS and MDA levels, and increased NF-\u03baB\u2013driven neuroinflammation and microglial Iba-1 expression. Mn was further associated with reduced ATP synthesis, dysregulation of SIRT1\/PGC-1\u03b1 signaling, and disrupted neurotransmitter balance, with a pro-apoptotic shift (elevated Bax, caspase-3, cytochrome c; reduced Bcl-2) and neuronal degeneration. Co-treatment with HNK, and more prominently with HNK-LNPs, was associated with reversing these alterations, restoring antioxidant and mitochondrial pathways, dampening inflammatory cascades, normalizing neurotransmitters, and favoring neuronal survival, with many indices approaching control values and consistently surpassing free HNK. Conclusions: Liposomal encapsulation significantly enhances honokiol\u2019s neuroprotection against Mn-induced hippocampal neurotoxicity, likely via improved CNS bioavailability and coordinated modulation of NRF2\/HO-1 and SIRT1\/PGC-1\u03b1 pathways. These findings support HNK-LNPs as a promising multi-mechanistic therapeutic strategy for metal-induced and related neurotoxic brain disorders.<\/jats:p>","DOI":"10.3390\/brainsci16090900","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:49:34Z","timestamp":1787582974000},"page":"900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Liposomal Honokiol Nanoparticles Attenuate Manganese-Induced Hippocampal Neurotoxicity via NRF2\/HO-1 and SIRT1\/PGC-1\u03b1 Pathways: Association with Oxidative Stress, Neuroinflammation, Mitochondrial Dysfunction, and Apoptosis"],"prefix":"10.3390","volume":"16","author":[{"given":"Raed","family":"Al Ruwaili","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Northern Border University, Arar 91431, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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\/0000-0002-4341-2713","authenticated-orcid":false,"given":"Mohamed M.","family":"Abdel-Daim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia"},{"name":"Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-5040","authenticated-orcid":false,"given":"Eida M.","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Sciences, University of Ha\u2019il, Ha\u2019il 2440, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aly A. M.","family":"Shaalan","sequence":"additional","affiliation":[{"name":"Department of 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\/0000-0003-0067-2838","authenticated-orcid":false,"given":"Ola A.","family":"Habotta","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Horus Research Center, Horus University\u2014Egypt (HUE), New Damietta 34518, 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\/0000-0002-2425-5994","authenticated-orcid":false,"given":"Mai","family":"Salem","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Baj, J., Flieger, W., Barbachowska, A., Kowalska, B., Flieger, M., Forma, A., Teresi\u0144ski, G., Portincasa, P., Buszewicz, G., and Radzikowska-B\u00fcchner, E. 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