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These promising outcomes were due to their ability to modulate various intracellular signalling pathways. Hence, the current study aimed to evaluate the neuroprotective effects of lapatinib and pazopanib in the 3-nitropropionic (3-NP)-induced HD model in rats. After 14\u00a0days of 3-NP administration, rats received saline, lapatinib, or pazopanib for 21\u00a0days. Treatment with lapatinib or pazopanib improved the striatal microscopic architecture, neuronal survival, and neuroinflammatory responses, with a pronounced effect observed for pazopanib. At the molecular level, lapatinib and pazopanib reduced the striatal gene expression of NF-\u03baB and TNF-\u03b1 receptors, curbed the glutamate\/calpain-2 axis, and modified the striatal content of inflammatory molecules as well as neurotransmitters. In addition, they activated the neuroprotective trajectory viz\n                    <jats:italic>.<\/jats:italic>\n                    , m-Tor\/ULK-1\/Beclin-1\/LC3-II, an effect dependent on tyrosine kinase inhibition. Moreover, treated groups showed normalised tyrosine hydroxylase and glial fibrillary acidic protein in the striatum. In conclusion, this study provides strong evidence that lapatinib or pazopanib significantly improved motor function, alleviated cognitive decline, and attenuated neurodegeneration in HD rats via modulating key signalling pathways implicated in HD pathogenesis. These results underscore the promising therapeutic potential of TKIs in managing HD and warrant further investigation into their clinical application.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    Schematic representation summarising the mechanisms underlying the neuroprotective effects of Lapatinib and Pazopanib in 3-NP induced Huntington disease in rats.\n                    <jats:italic>LAP<\/jats:italic>\n                    Lapatinib,\n                    <jats:italic>PAZO<\/jats:italic>\n                    pazopanib,\n                    <jats:italic>ACh<\/jats:italic>\n                    acetylcholine,\n                    <jats:italic>NE<\/jats:italic>\n                    norepinephrine,\n                    <jats:italic>DA<\/jats:italic>\n                    dopamine,\n                    <jats:italic>5-HT<\/jats:italic>\n                    5-hydroxytryptophan,\n                    <jats:italic>Glu<\/jats:italic>\n                    glutamate,\n                    <jats:italic>LC3<\/jats:italic>\n                    microtubule-associated protein 1A\/1B-light chain,\n                    <jats:italic>ULK-1<\/jats:italic>\n                    Unc-51 like autophagy activating kinase,\n                    <jats:italic>m-Tor<\/jats:italic>\n                    mammalian target of rapamycin,\n                    <jats:italic>AKT<\/jats:italic>\n                    protein kinase B,\n                    <jats:italic>PI3K<\/jats:italic>\n                    phosphoinositide 3-kinase,\n                    <jats:italic>TNF-\u03b1<\/jats:italic>\n                    tumour necrosis alpha,\n                    <jats:italic>NF\u03baB<\/jats:italic>\n                    nuclear factor kappa B,\n                    <jats:italic>GFAP<\/jats:italic>\n                    glial fibrillary acidic protein,\n                    <jats:italic>TH<\/jats:italic>\n                    tyrosine hydroxylase.\n                  <\/jats:p>","DOI":"10.1007\/s10787-025-01933-5","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T11:02:03Z","timestamp":1757502123000},"page":"6211-6226","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Potential repurposing of lapatinib and pazopanib as neuroprotective agents in a rat model of Huntington\u2019s disease"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0458-9610","authenticated-orcid":false,"given":"Nada","family":"Ezeldine-Elmahalawy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noha F.","family":"Abdelkader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany I.","family":"Elbrairy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameh S.","family":"Gad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"issue":"5","key":"1933_CR1","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1007\/s10787-023-01269-y","volume":"31","author":"R Abdelhady","year":"2023","unstructured":"Abdelhady R, Younis NS, Ali O et al (2023) Cognitive enhancing effects of pazopanib in d-galactose\/ovariectomized Alzheimer\u2019s rat model: insights into the role of RIPK1\/RIPK3\/MLKL necroptosis signalling pathway. 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