--- - |2 Abstract Parkinson's disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Cathepsin D (CathD), a soluble aspartic protease, has been reported to play an important role in neurodegenerative diseases such as PD. This research focused on the role of CathD and the molecular mechanisms involved in the process of neuroinflammation and neurotoxicity. We used 1‐methyl‐4phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP)‐challenged mice and lipopolysaccharide (LPS)‐induced murine microglia BV2 cells as the in vivo and in vitro models, respectively. The effect of CathD on the neuroinflammation, cytotoxicity and the underlying mechanisms associated with NF‐κB signaling pathway were investigated. Date showed that MPTP induces motor deficit, inflammation and depletion of dopaminergic neurons in PD model mice. Notably, cathD was overexpressed in the SNpc of MPTP‐induced PD mice and was highly expressing in LPS‐stimulated primary microglial cells and BV‐2 cells. Furthermore, knockdown of CathD with lentiviral transduction inhibited LPS‐induced neuroinflammation through inhibition of NF‐κB signaling pathway primarily by regulating the NF‐κB p65 nuclear translocation both in BV‐2 and primary microglial cells. Additionally, knockdown of CathD protected the activated‐microglia induced dopaminergic neurons MN9D cells from neurotoxicity as well as apoptosis. Our findings bring a new insight into understanding the complex mechanisms underlying the pathogenesis of PD and provide a novel target to attenuate the excessive neuroinflammatory responses in the treatment of PD. This article is protected by copyright. All rights reserved. - 'Clinical and Experimental Pharmacology and Physiology, Volume 0, Issue ja, -Not available-. '