Beauvericin promotes autophagy and mitophagy by activating NIPSNAP2

Dysregulation of autophagy and mitophagy is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). Chemical intervention targeting these pathways has emerged as one of the promising therapeutic strategies for neurodegenerative disorders. Here, we identified beauvericin as a candidate molecule that regulates autophagy and mitophagy through an organelle phenotypes-based high-throughput screening of a marine natural products library. Mechanistic analyses revealed that beauvericin engages NIPSNAP2 and promotes its activation, and enhances autophagic flux and mitophagy across multiple cell types. Moreover, in AD-relevant cellular models, beauvericin significantly reduced amyloid-β (Aβ) levels via lysosome-dependent degradation of BACE1. Collectively, these findings demonstrate that beauvericin activates autophagy and mitophagy via NIPSNAP2 and that chemical activation of these pathways can ameliorate AD-relevant cellular phenotypes, supporting its potential as a chemical intervention for neurodegenerative diseases.