Chronic TFE3 activation in TFE3-associated neurodevelopmental disorder drives metabolic rigidity, lysosomal failure, and cell-extracellular matrix destabilization

However, emerging data suggest that TFE3 dysregulation is a primary driver of various pathological conditions. Our study unveils how chronic-activation of TFE3, an otherwise protective stress-response factor, directly impairs cellular homeostasis, leading to a combination of high metabolic output and failed structural anchoring, thus disrupting cellular networks.

This distinctive state provides a mechanistic basis for the tissue-level malformations and neurodevelopmental deficits that define the pathology of TFE3-NDD.