Spatial Metabolomics and Single-Cell Virtual Knockout Screening Reveal Solanesol Improves Parkinson's Disease-like Pathology Based on Lipid Inflammation Mechanism.

Overview

1. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
2. Beijing Life Science Academy, Beijing 102209, China; (L.X.); (M.Z.); (G.W.)
3. Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center, Zhengzhou 450099, China

Abstract

Background: Parkinson’s disease (PD) is characterized by a complex interplay of dopaminergic degeneration, glial activation, and lipid metabolic dysregulation. However, accurately describing how natural product interventions remodel these pathologies across distinct brain regions and cellular microenvironments remains a critical challenge. Methods: We established an integrated multi-omics framework to decode the neuroprotective mechanisms of solanesol (Sol) in an MPTP-induced PD mouse model. We combined single-cell eQTL-based Mendelian randomization (scMR), transcriptomic localization, and virtual knockout analyses to prioritize cell-type-specific regulatory nodes across neuronal, glial, and vascular populations, avoiding the limitations of traditional bulk targeting. In vivo behavioral assays were conducted, alongside orthogonal validation via airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) and gene–metabolite co-enrichment analysis, to map regional metabolic networks and structural spatial reprogramming. Results: Computational prioritization highlighted cell-type-specific regulatory nodes including PRKCB, PRKCE, PDGFRB, and FABP3/5. In vivo, Sol attenuated motor and cognitive deficits and largely restored the highly compartmentalized spatial distributions of striatal dopamine, L-DOPA, and acetylcholine. Crucially, AFADESI-MSI and co-enrichment analysis revealed that Sol specifically reversed MPTP-induced spatial disruptions by rescuing key neuromodulatory metabolites—including cervonoyl ethanolamide, phosphatidylcholine species, taurine, and NADHX—which were tightly coupled to sphingolipid signaling, fatty-acid transport, mitochondrial translation, and cell-adhesion pathways. Conclusions: Sol ameliorates PD-like pathology not through a singular target, but by choreographing a spatially and cellularly compartmentalized restoration of lipid–inflammatory homeostasis. Furthermore, our integrated single-cell and spatial metabolomic blueprint sets a new methodological paradigm for elucidating the precise execution programs of natural neurotherapeutics.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE243639 — at NCBI GEO; found in the text, “2.5. Single-Cell Virtual Knockout Analysis”

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 6 keywords, 4 funders, 58 references.

Cite

This paper

Li, Q., Xu, L., Zhu, M., Wang, G., Chen, H., Hou, H., & Bai, Y. (2026). Spatial Metabolomics and Single-Cell Virtual Knockout Screening Reveal Solanesol Improves Parkinson's Disease-like Pathology Based on Lipid Inflammation Mechanism. Metabolites, 16(8), 541. https://doi.org/10.3390/metabo16080541

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