From Cancer to Neuroprotection: Pazopanib Modulates the RIPK1/RIPK3/MLKL and PGAM5/DRP1 Pathways in 3‐ Nitropropionic Acid‐Induced Huntington's Disease

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Abstract
Huntington's disease (HD) is a progressive neurodegenerative disorder with a poorly understood neurobiological basis. Among the various forms of programmed cell death implicated in neurodegeneration, necroptosis has recently garnered significant attention. Notably, dysregulated necroptosis provokes immune response that drives excessive pro‐inflammatory cytokine production, promoting further necroptotic cell death through TNF‐α/RIPK1 signaling. Consequently, necroptosis exacerbates neuroinflammation, contributing to the progression of different neurodegenerative diseases. However, the precise role of necroptosis in HD pathogenesis remains unclear. Given the growing interest in repurposing FDA‐approved drugs for novel therapeutic interventions, this study investigates the anti‐cancer agent Pazopanib (Pazo) as a potential neuroprotective approach for HD. This study assesses Pazo's ability to mitigate necroptosis by targeting the RIPK1/RIPK3/MLKL pathway in a model of HD produced by 3‐nitropropionic acid (3‐NP). Sixty male Wistar rats were randomly assigned to four groups: Group I received normal saline; Group II received Pazo (15 mg/kg, i.p.); Group III received 3‐NP (10 mg/kg, i.p.); and Group IV received 3‐NP (10 mg/kg, i.p.) and Pazo (15 mg/kg, i.p.). Behavioral assessments, including open field, rotarod, and wire hanging tests, demonstrated that Pazo significantly improved motor function. At the molecular level, Pazo inhibited PGAM5, a key regulator of mitochondrial fission, effectively reversing the RIPK1/RIPK3/MLKL necroptotic cascade and the consequent immune activation. This suppression of necroptosis was associated with reduced microgliosis, neuroinflammation and enhanced neuronal survival within the striatum. These findings highlight the potential of Pazo as a neuroprotective agent against HD by leveraging its antioxidant, anti‐inflammatory, immune‐modulating, and anti‐necroptotic properties.

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