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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\u2013metabolite 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\u2014including cervonoyl ethanolamide, phosphatidylcholine species, taurine, and NADHX\u2014which 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\u2013inflammatory homeostasis. Furthermore, our integrated single-cell and spatial metabolomic blueprint sets a new methodological paradigm for elucidating the precise execution programs of natural neurotherapeutics.<\/jats:p>","DOI":"10.3390\/metabo16080541","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T13:23:20Z","timestamp":1785504200000},"page":"541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Metabolomics and Single-Cell Virtual Knockout Screening Reveal Solanesol Improves Parkinson\u2019s Disease-like Pathology Based on Lipid Inflammation Mechanism"],"prefix":"10.3390","volume":"16","author":[{"given":"Qian","family":"Li","sequence":"first","affiliation":[{"name":"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"},{"name":"Beijing Life Science Academy, Beijing 102209, China"},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center, Zhengzhou 450099, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutao","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy, Beijing 102209, China"},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center, Zhengzhou 450099, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy, Beijing 102209, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoge","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy, Beijing 102209, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy, Beijing 102209, China"},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center, Zhengzhou 450099, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Hou","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy, Beijing 102209, China"},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center, Zhengzhou 450099, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1542-0297","authenticated-orcid":false,"given":"Yu","family":"Bai","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","article-title":"Parkinson disease","volume":"3","author":"Poewe","year":"2017","journal-title":"Nat. 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