Autophagy regulators

Autophagy regulators represent a broad class of proteins and signaling complexes that orchestrate macroautophagy, an evolutionarily conserved catabolic process essential for maintaining cellular homeostasis [1, 10]. This machinery includes key regulatory nodes such as the mTORC1 complex, which acts as a nutrient sensor to inhibit autophagy, and the ULK1 initiation complex, which triggers autophagosome formation upon activation by AMPK [5, 8]. The pathway involves the sequestration of damaged organelles, misfolded proteins, and pathogens into double-membraned autophagosomes, which subsequently fuse with lysosomes for degradation and nutrient recycling [3, 17]. In clinical contexts, autophagy regulators are significant therapeutic targets due to their dual roles in diseases like cancer, where they can either suppress early tumorigenesis or promote the survival of established tumors under stress [2, 12]. They are also critical in neurodegenerative diseases, where impaired autophagic flux leads to the toxic accumulation of protein aggregates [4, 19]. Pharmacological modulation of these regulators includes the use of mTOR inhibitors like rapamycin to induce autophagy and lysosomotropic agents like hydroxychloroquine to inhibit it [6, 11]. Given the fundamental role of autophagy in normal physiology, targeting these regulators requires careful consideration of systemic safety and context-specific effects [17, 19].

Other names

Autophagy-related proteinsAutophagy machineryATG proteinsAutophagy pathway components

Autophagy regulators are modulated through two primary pharmacological approaches: induction and inhibition of the autophagic pathway. Inducers typically target upstream nutrient-sensing pathways, such as mTORC1 inhibition (e.g., by rapamycin or rapalogs) or AMPK activation (e.g., by metformin), which relieves the suppression of the ULK1 initiation complex [1, 6, 8]. Conversely, inhibitors act at various stages of the process, such as blocking the class III PI3K (VPS34) complex to prevent autophagosome nucleation (e.g., by wortmannin or 3-methyladenine) or disrupting lysosomal function and autophagosome-lysosome fusion (e.g., by chloroquine, hydroxychloroquine, or bafilomycin A1) [1, 6, 12, 19].