Small-molecule autophagy modulators: Mechanisms, therapeutic potential, and development challenges in pathological settings.

Autophagy is an evolutionarily conserved process in eukaryotic cells that delivers intracellular components to lysosomes for degradation and recycling. Increasing evidence has elucidated the regulation of autophagy, highlighting its involvement in cellular metabolism, survival, and development, as well as its association with diverse physiological and pathological processes. There are often mutations in autophagy-regulating genes or abnormal autophagy function in multiple diseases, such as cancer, immune system diseases, and neurodegenerative diseases. Additionally, the regulation of the autophagy process shows potential therapeutic effects for these diseases. Several small molecules have been developed as autophagy regulators based on traditional drug discovery strategies, such as high-throughput screening, structure-activity relationship (SAR) optimization, and computer-aided drug design. Mechanistically, these compounds that bind specifically to such autophagy-related proteins or kinases can act as agonists or antagonists, with downstream consequences on the autophagy process. Several pharmacologic agents that regulate the autophagy process with extraordinary potential in disease treatment have come into clinical use. But most of these molecules still suffer from many obstacles, including low efficacy, low selectivity, poor pharmacokinetic profile, drug resistance, and toxicity. Moreover, some inappropriate and undruggable autophagy-related targets, as well as ubiquitous protein aggregates in neurodegenerative diseases, also bring serious challenges to the identification of small-molecule drugs. In this review, we briefly introduce autophagy and summarize its function and regulatory role in various diseases and disorders, and discuss the possibility of autophagy-targeted therapy in these diseases. The present review highlights current developments regarding the fundamental molecular mechanisms and signaling cascades of autophagy, while also addressing strategies for small-molecule-based therapeutic intervention.