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Despite significant progress in understanding the molecular and cellular disruptions associated with PD, there remains an unmet clinical need for effective therapies. In this study, proteomic analysis of the olfactory tract (OT) in controls with no known neurological history (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200917) and PD subjects (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200921) revealed Lewy body disease (LBD) stage\u2010dependent proteostatic impairment, accompanied by progressive modulation of the alpha\u2010synuclein (\u03b1\u2010syn) functional interactome. Differential OT omic profiles were used in a computational drug repurposing approach, revealing the HDAC1 inhibitor pyroxamide as one of the top drug candidates with in silico potential to restore altered OT omic profiles. To explore the potential therapeutic effects of pyroxamide, in vitro assays were performed using \u03b1\u2010syn preformed fibrils (PFFs). Pyroxamide treatment reduced \u03b1\u2010syn PFFs\u2010induced toxicity in olfactory epithelial, microglial and dopaminergic neuronal cell lines, producing a protective effect against hydrogen peroxide\u2010induced damage exclusively in brain\u2010derived cell types. Mechanistically, the mitigating effects of pyroxamide were attributable, at least in part, to the regulation of Bax\u20101 and sirtuin 1 (SIRT1) protein expression, along with alterations in the mRNA levels of NEF2L2, IL1B, and TNF\u2010\u03b1. These findings confirm the suitability of omics profiles in drug repurposing workflows against PD, offering valuable insights into the potential of HDAC1 inhibitors in the therapeutic pipeline of PD.\n                  <\/jats:p>","DOI":"10.1111\/bpa.70140","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T03:52:34Z","timestamp":1788148354000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Olfactory proteomics reveals the capacity of the\n                    <scp>HDAC1<\/scp>\n                    inhibitor pyroxamide to halt the \u03b1\u2010synuclein preformed fibrils\u2010induced damage in nasal epithelial, microglial and dopaminergic neuronal cell lines"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-7445","authenticated-orcid":false,"given":"Paz","family":"Cartas\u2010Cejudo","sequence":"first","affiliation":[{"name":"Clinical Neuroproteomics 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