Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer's Disease.
Overview
- Department of Geriatrics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
- The First Clinical Medical College, Anhui Medical University, Hefei 231241, China
- Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
- Tianjin Interdisciplinary Innovation Centre for Health and Meteorology, Tianjin 300211, China
Abstract
Alzheimer’s disease (AD) is characterized not only by neuronal dysfunction but also by profound remodeling of the brain microenvironment, including immune–glial 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 Aβ1–42-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.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE175814, at NCBI GEO; found in “Data Availability Statement”
Data Availability Statement
Publicly available datasets were analyzed in this study. Bulk transcriptomic data were obtained from the Gene Expression Omnibus (GEO) under accession numbers GSE122063 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 13 keywords, 8 MeSH terms, 6 funders, 56 references.
Cite
This paper
Gao, R., Lyu, C., Gu, Y., Hao, R., Wang, C., & Li, X. (2026). Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer's Disease. International journal of molecular sciences, 27(11), 4756. https://
BibTeX
@article{gao2026multi,
author = {Gao, Renjie and Lyu, Chenqu and Gu, Yumeng and Hao, Ruixiao and Wang, Chao and Li, Xin},
title = {{Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer's Disease}},
journal = {International journal of molecular sciences},
year = {2026},
month = may,
volume = {27},
number = {11},
pages = {4756},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {1422-0067},
doi = {10.3390/
url = {https://
pmid = {42278287},
pmcid = {PMC13256803}
}
RIS
TY - JOUR
AU - Gao, Renjie
AU - Lyu, Chenqu
AU - Gu, Yumeng
AU - Hao, Ruixiao
AU - Wang, Chao
AU - Li, Xin
TI - Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer's Disease
T2 - International journal of molecular sciences
J2 - Int J Mol Sci
PY - 2026
DA - 2026/
VL - 27
IS - 11
SP - 4756
SN - 1422-0067
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/
UR - https://
LA - en
ER -
CSL-JSON
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"container-title": "International journal of molecular sciences",
"author": [
{
"family": "Gao",
"given": "Renjie"
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{
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"given": "Chenqu"
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{
"family": "Gu",
"given": "Yumeng"
},
{
"family": "Hao",
"given": "Ruixiao"
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"given": "Chao"
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{
"family": "Li",
"given": "Xin"
}
],
"container-title-short":
"volume": "27",
"issue": "11",
"page": "4756",
"DOI": "10.3390/
"PMID": "42278287",
"PMCID": "PMC13256803",
"ISSN": "1422-0067",
"publisher": "Multidisciplinary Digital Publishing Institute (MDPI)",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
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2026,
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}
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