The ATG14: multi-layer autophagy control and an emerging therapeutic target in cancer.

ATG14 (ATG14L/Barkor) is the autophagy-specific subunit of class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) and functions as a pivotal node linking autophagosome formation to autophagosome-lysosome fusion. Functionally, ATG14 regulates cell fate through multiple mechanisms. Under hypoxic or nutrient-deprived conditions, ATG14 maintains tumor cell survival and drug resistance, remodels cellular metabolism via lipophagy and mitophagy, and can either suppress or promote programmed cell death depending on the cellular context. Moreover, ATG14 plays protective roles in maintaining neuronal and hepatic homeostasis and is involved in the development of inflammatory and metabolic disorders. Here, we discuss the multi-layered regulation of ATG14, including post-translational modifications (phosphorylation, ubiquitination, palmitoylation), epitranscriptomic and non-coding RNA regulation, and competitive complex interactions, all of which fine-tune its autophagic output and functional plasticity. We further highlight the central roles of ATG14 during the autophagic process, summarize recent advances in cancer-related ATG14 research, and review ongoing drug development efforts as well as potential therapeutic strategies targeting ATG14. Our goal is to provide a comprehensive understanding of the physiological and pathological functions of ATG14 and to explore its potential as a druggable signaling hub. Given its bidirectional regulatory capacity to either suppress cytoprotective autophagy or enforce lethal autophagy-ATG14-targeted interventions must be strategically designed based on the disease stage and autophagy dependence.