{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:27:24Z","timestamp":1785421644491,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["42275197"],"award-info":[{"award-number":["42275197"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["42275197"],"award-info":[{"award-number":["42275197"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Key Projects of Tianjin Municipal Health Commission","award":["TJWJ2023XK007"],"award-info":[{"award-number":["TJWJ2023XK007"]}]},{"name":"Key Discipline of Geriatrics in Tianjin Municipality","award":["TJYXZDXK-3-017C"],"award-info":[{"award-number":["TJYXZDXK-3-017C"]}]},{"name":"Tianjin Key Medical Discipline Construction Project","award":["TJYXZDXK-065B"],"award-info":[{"award-number":["TJYXZDXK-065B"]}]},{"DOI":"10.13039\/501100019065","name":"Tianjin Science and Technology Plan Project","doi-asserted-by":"publisher","award":["25JCQNJC00780"],"award-info":[{"award-number":["25JCQNJC00780"]}],"id":[{"id":"10.13039\/501100019065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tianjin Center for Health and Meteorology Multidisciplinary Innovation, Building a Climate Change Early Warning System for the Aged - Climate change and aged care research and modeling firm","award":["TA-10207 PRC"],"award-info":[{"award-number":["TA-10207 PRC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is characterized not only by neuronal dysfunction but also by profound remodeling of the brain microenvironment, including immune\u2013glial activation and metabolic dysregulation. Increasing evidence also implicates neurosteroid-related pathways in AD and dementia. Nobiletin has shown neuroprotective effects in AD-related models, but its upstream human targets and mechanism-based translational relevance remain insufficiently defined. Here, we integrated multi-omics analyses, interpretable machine learning, causal inference, structural modeling, and experimental validation to identify candidate nobiletin-associated molecular nodes in AD. HSD17B1 consistently emerged as a central AD-associated candidate across multiple analytical layers and showed reproducible discriminatory performance in independent validation cohorts. SHAP analysis further identified HSD17B1 as a major contributor to the optimal predictive model, while Mendelian randomization supported a protective association between genetically increased HSD17B1 expression and AD risk. Immune infiltration, single-cell, and spatial transcriptomic analyses linked HSD17B1 to glia-associated remodeling and regionally heterogeneous expression patterns in AD. Molecular docking and molecular dynamics simulations supported the structural feasibility of nobiletin binding to HSD17B1, and in an A\u03b21\u201342-induced SH-SY5Y cell model, nobiletin increased HSD17B1 expression at both the mRNA and protein levels. Together, these findings support HSD17B1 as an AD-associated and nobiletin-responsive candidate molecular node, highlight a potential connection between nobiletin and neurosteroid-related regulation, and provide an integrated framework for target prioritization and validation in AD.<\/jats:p>","DOI":"10.3390\/ijms27114756","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T14:10:22Z","timestamp":1779718222000},"page":"4756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5384-5815","authenticated-orcid":false,"given":"Renjie","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Geriatrics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5028-7663","authenticated-orcid":false,"given":"Chenqu","family":"Lyu","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Anhui Medical University, Hefei 231241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumeng","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixiao","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China"},{"name":"Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China"},{"name":"Tianjin Interdisciplinary Innovation Centre for Health and Meteorology, Tianjin 300211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2024). 2024 Alzheimer\u2019s disease facts and figures. 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