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Altered signaling through hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) and PI3K\/AKT cascades contributes to neuronal vulnerability. Canagliflozin (Cana), a sodium\u2013glucose cotransporter-2 inhibitor, has shown cognitive benefits in experimental studies. Here, we evaluated whether Cana mitigates 3-nitropropionic acid (3NP, 10\u00a0mg\/kg, i.p., 14\u00a0days)-induced HD-like neurotoxicity in rats. Animals received Cana (5 or 10\u00a0mg\/kg, p.o.) daily for 14\u00a0days, followed by behavioral assessments (open-field, Morris water maze, novel object recognition), histopathology, immunohistochemistry, and biochemical assays. Cana treatment significantly improved locomotor and memory performance, reduced striatal histopathological alterations, and attenuated GFAP immunoreactivity. Mechanistically, Cana upregulated HIF-1\u03b1 and downstream GLUT1\/GLUT3\/HKII, restored PI3K\/AKT\/CREB\/BDNF signaling, and enhanced SIRT1\/PGC-1\u03b1\/Nrf2 antioxidant responses, while suppressing inflammatory mediators and caspase-3 activation. These findings highlight Cana as a promising disease-modifying strategy for HD by targeting both energy metabolism and pro-survival pathways.<\/jats:p>","DOI":"10.1007\/s00210-025-04891-5","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T06:48:21Z","timestamp":1766731701000},"page":"8245-8262","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neuroprotection by canagliflozin in a Huntington\u2019s disease model: role of HIF-1\u03b1 and PI3K\/AKT signaling"],"prefix":"10.1007","volume":"399","author":[{"given":"Ali M.","family":"Elgindy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El-Sayed E.","family":"El-Awady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norhan M.","family":"El-Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naglaa F.","family":"El-Orabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Atwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"4891_CR1","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1007\/s00210-018-1521-5","volume":"391","author":"AA Abdelsameea","year":"2018","unstructured":"Abdelsameea AA, Kabil SL (2018) Mitigation of cisplatin-induced peripheral neuropathy by canagliflozin in rats. 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