Restoring amyloid clearance: Z17 promotes astrocytes to clear Alzheimer's plaques via CHI3L1 inhibition.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, accumulation of hallmark protein aggregates and substantial neuroinflammation. Chitinase-3-like protein 1 (CHI3L1) which is predominantly produced by activated astrocytes in the central nervous system (CNS). While elevated CHI3L1 is an established biomarker associated with AD progression, its potential role as a pathogenic driver remains a subject of investigation. Herein, we report the identification of Z17 as a novel and selective CHI3L1 inhibitor which directly bind to CHI3L1 an equilibrium dissociation constant (KD) of 6.0 μM. In human iPSC-derived astrocytes, Z17 mitigated phenotypes induced by exogenous CHI3L1, restoring astrocytic function and suppressing inflammatory signaling. Additionally, Z17 rescued CHI3L1-induced impairment by dose-dependently restoring Aβ uptake and normalizing lysosomal proteolytic activity and pH. Furthermore, Z17 effectively blocked CHI3L1-driven activation of the NF-κB pathway in human astrocytes, offering insights into a potential mechanism for the functional rescue. The in vitro pharmacokinetic (PK) profiling of Z17 demonstrated favorable drug-like properties predictive of potential CNS development. These findings support the advancement of Z17 as a selective CHI3L1 inhibitor capable of simultaneously mitigating neuroinflammation and restoring astrocytic clearance mechanisms, making it a highly promising therapeutic candidate for Alzheimer's disease.