Abstract

Autophagy is the evolutionarily conserved process by which eukaryotic cells deliver cytoplasmic constituents to the lysosome for degradation and recycling. Once regarded as a nonselective response to starvation, it is now understood as a tightly regulated and frequently selective quality-control system that shapes proteostasis, organelle turnover, metabolism, immunity, and lifespan. This narrative review synthesises mechanistic and disease-oriented literature, emphasising work from 2019 onward while retaining the landmark genetic and cell-biological studies on which the field rests. We first dissect autophagosome biogenesis as a stepwise reaction—initiation by the ULK1 complex, nucleation by the class III phosphatidylinositol 3-kinase complex, membrane expansion driven by lipid transfer and ubiquitin-like conjugation of ATG8 proteins, closure, and fusion with the lysosome—because each step has become a candidate node for pharmacological intervention. We then examine cargo selectivity, the property that most clearly distinguishes contemporary understanding from the classical bulk-degradation model, and compare macroautophagy with microautophagy and chaperone-mediated autophagy. Against this mechanistic backdrop we appraise the evidence linking autophagy to neurodegeneration, cancer, infection and inflammation, metabolic and cardiovascular disease, and ageing. A central and recurring theme is context dependence: the same pathway that suppresses tumour initiation can sustain established tumours, and the therapeutic imperative is accordingly to induce autophagy in some settings and inhibit it in others. We critically compare discordant clinical results with autophagy inhibitors, notably the divergent outcomes of hydroxychloroquine trials in pancreatic cancer, and argue that much of this inconsistency reflects unresolved problems of drug specificity, flux measurement, and patient selection rather than a failure of the underlying biology. We conclude by identifying priority research gaps, foremost among them the need for selective, mechanism-based modulators and validated biomarkers of autophagic flux in humans.

Keywords: Autophagy, Autophagosome, Lysosome, Mitophagy, Selective autophagy, Chaperone-mediated autophagy, Neurodegeneration, Hydroxychloroquine