Decoding Class III Phosphatidylinositol 3‐Kinase (PtdIns3K) Regulation: Mechanistic Insights and Therapeutic Opportunities

Class III phosphatidylinositol 3-kinase (PtdIns3K) occupies the nexus of autophagy and endomembrane trafficking. Within its core complex, the VPS34 catalytic subunit partners with VPS15, Beclin-1, and ATG14L or UVRAG to convert phosphatidylinositol into PtdIns3P-the lipid cue that seeds phagophore nucleation and endosome-lysosome maturation. By tuning this single signaling node, cells safeguard proteostasis and orchestrate rapid stress responses; when this regulatory network is disrupted, PtdIns3K dysregulation fuels neurodegeneration, tumor progression, immune imbalance, and metabolic disease. This review fuses cutting-edge structural and biochemical insights into PtdIns3K, dissects its multilayered regulation-spanning post-translational modifications, adaptor engagement, and higher-order assembly-and appraises next-generation small-molecule inhibitors designed for precision autophagy control. Decoding and therapeutically exploiting this pathway will open a new chapter in the discovery of innovative therapeutic approaches.