Mitoxantrone Hydrochloride Targets APP and LRRK2 to Improve Neurodegeneration in Parkinson's Models

Parkinson's disease (PD) is a debilitating neurodegenerative disorder lacking therapies that can halt its progression, driven by the loss of dopaminergic neurons and pathological protein accumulation. Our previous research uncovered a critical pathogenic feed-forward loop between the amyloid precursor protein (APP) and leucine-rich repeat kinase 2 (LRRK2), where they mutually drive each other's expression, culminating in mitochondrial dysfunction and neurotoxicity. Targeting this vicious cycle represents a promising therapeutic strategy. To discover a potent inhibitor of this axis, we performed high-throughput screening of an FDA-approved drug library. This identified Mitoxantrone hydrochloride (MH), an antineoplastic agent, as a lead compound. We demonstrate that MH dually suppresses both APP transcription and LRRK2 expression/kinase activity, the latter via direct binding to the LRRK2 kinase domain. In cellular models, including patient-derived neurons, MH mitigated neurotoxicity by reducing apoptosis. Critically, in both toxin-induced and genetic PD mouse models, MH treatment rescued dopaminergic neuron loss, reduced phospho-α-synuclein, and reversed motor deficits. Oral administration was particularly effective, showing superior neuroprotection and behavioral recovery with no detectable cardiotoxicity or gastrointestinal damage. Our findings establish MH as a compelling, repurposable therapeutic candidate capable of disrupting a core pathogenic mechanism in PD.