Pharmacological strategies targeting chaperone-mediated autophagy

Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradation pathway that regulates proteostasis, metabolism, and stress adaptation. Genetic- and disease-model studies show that altered CMA activity contributes to diverse human disorders, including neurodegenerative, metabolic, inflammatory, and malignant diseases. However, pharmacological targeting has remained challenging due to a limited understanding of its regulatory architecture and a lack of criteria to distinguish pathway-selective from indirect modulation. Recent advances in mapping CMA regulatory checkpoints and the in vivo validation of CMA-biased compounds have revealed discrete, mechanistically defined control nodes that render CMA pharmacologically tractable. In this review, we synthesize these advances and introduce a mechanistic classification of CMA-modulating compounds by level of action, distinguishing physiological inducers, permissive potentiators, and proximal activators to clarify pathway selectivity and guide translational drug discovery.