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This study explores the development of dual\u2010acting compounds combining sigma\u20101 receptor (\n                    <jats:italic>\u03c3<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    R) agonists and histone deacetylase inhibitors (HDACi) to target these pathological mechanisms. Compounds\n                    <jats:bold>2d<\/jats:bold>\n                    and\n                    <jats:bold>3a<\/jats:bold>\n                    demonstrated high affinity for\n                    <jats:italic>\u03c3<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    R and significantly reduced tau aggregation and phosphorylation in vitro, notably at the AT8 epitope. These dual\u2010acting compounds destabilized tau aggregates, increased tau solubility, and showed favorable pharmacokinetic properties, with compound\n                    <jats:bold>2d<\/jats:bold>\n                    exhibiting enhanced chemical stability and longer half\u2010life than\n                    <jats:bold>3a<\/jats:bold>\n                    . In vivo, both compounds confirmed a\n                    <jats:italic>\u03c3<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    R agonist profile by reversing the effect of the\n                    <jats:italic>\u03c3<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    R antagonist BD\u20101063. This dual\u2010action approach, acting on both HDAC and\n                    <jats:italic>\u03c3<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    R pathways, holds significant potential for treating tauopathies. While further optimization and clinical evaluation are needed, these findings provide a strong foundation for the continued development of multimodal therapies for neurodegenerative diseases treatment.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500922","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T19:36:02Z","timestamp":1773430562000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modulation of Tau Protein Neurotoxic Hallmarks by Novel\n                    <i>\u03c3<\/i>\n                    <sub>1<\/sub>\n                    R Agonists\/HDAC Inhibitor Dual\u2010Acting Compounds"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1899-8414","authenticated-orcid":false,"given":"Antonino N.","family":"Fallica","sequence":"first","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"},{"name":"Institute for Bioengineering of Catalonia (IBEC) The Barcelona Institute of Science and Technology  Barcelona Spain"},{"name":"Barcelona Institute for Global Health (ISGlobal) Hospital Cl\u00ednic\u2010Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6155-6702","authenticated-orcid":false,"given":"Carla","family":"Barbaraci","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-0946","authenticated-orcid":false,"given":"M. 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