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Accordingly, there is a growing interest in the potential neuroprotective benefits of newer anti\u2010diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP\u20104is) and sodium\u2013glucose cotransporter\u20102 inhibitors (SGLT2is). Although clinical studies suggest that these drugs mitigate cognitive decline, the underlying mechanisms remain unclear. This study aimed to elucidate the potential mechanisms through which DPP\u20104is or SGLT2is, in combination with metformin, confer neuroprotection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We conducted a cross\u2010sectional study involving T2D patients on either metformin alone or in combination with a DPP\u20104i or SGLT2i, alongside healthy controls. Cognitive and metabolic phenotypes were assessed, followed by serum proteomic profiling, computational drug target prediction, network analyses and molecular docking to identify signalling pathways linked to cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>T2D patients on combination therapy demonstrated better cognitive function, independent of other phenotypic, metabolic and biochemical factors. Proteomic profiling revealed 36 differentially expressed proteins that were preserved or restored to control levels in the combination therapy group. Gene set enrichment analysis highlighted the modulation of the complement pathway, particularly the involvement of ficolin\u20103 (FCN3). Molecular docking suggested that the sugar\u2010like or glycyl moieties in anti\u2010diabetic drug molecules interacted with FCN3, potentially inhibiting complement system activation. Such interaction was confirmed by binding studies using surface plasmon resonance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>These findings are significant in tailoring T2D treatment to reduce cognitive complications and exploring drug design to target neuroinflammatory disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70331","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:50:30Z","timestamp":1769475030000},"page":"2533-2555","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Repurposing SGLT2 and DPP\u20104 inhibitors for mild cognitive impairment in type 2 diabetes mellitus: Insights from proteomics, target prediction and molecular docking"],"prefix":"10.1111","volume":"183","author":[{"given":"Shams T.","family":"Osman","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perihan A.","family":"Elzahhar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Abdul","family":"Hakim","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas Tech University  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akeem","family":"Sanni","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas Tech University  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noha A.","family":"Hamdy","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waziha Tasnim","family":"Purba","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas Tech University  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Mostofa Al Amin","family":"Bhuiyan","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas Tech University  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherifdeen","family":"Onigbinde","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas Tech University  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal","family":"Sandilya","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas Tech University  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayera W.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Agami","sequence":"additional","affiliation":[{"name":"The Research and Innovation Hub Alamein International University  Alamein Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Labiba K.","family":"El\u2010Khordagui","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria","family":"Spagnuolo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology Alma Mater Studiorum\u2014University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Naldi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology Alma Mater Studiorum\u2014University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Bartolini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology Alma Mater Studiorum\u2014University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed S. 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