Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening

, we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.