Natural product screening reveals nanomolar Musashi2 inhibitor reducing forgetting in Caenorhabditis elegans

Physiological forgetting is an essential process for normal brain function, yet the molecular mechanisms underlying memory loss, including pathologically accelerated forms, are still not fully elucidated. A key mechanism to induce forgetting was identified in Caenorhabditis elegans (C. elegans) involving the RNA-binding protein Musashi (MSI), which acts as a translational regulator. Here, we report the discovery of a series of nanomolar inhibitors of MSI identified via a high-throughput natural product screening platform of a plant extract library. Ellagic acid (EA) emerged as one of the most potent inhibitors, improving both short- and long-term associative memory in an all-or-none like manner in an in vivo C. elegans memory model. Notably, EA had no effect in msi loss-of-function mutant worms, corroborating MSI as its molecular target. These findings underscore MSI as a therapeutic target for modulating forgetting and establish EA as a nanomolar MSI inhibitor and promising lead compound for mitigating memory decay.