Figure 2. Principles of autophagy modulation.

a | When autophagy mechanistically contributes to the aetiology of the disease, inhibiting autophagy initiation in diseased cells is expected to restore normal autophagic degradation and mediate therapeutic effects, whereas blocking lysosomal degradation may favour a detrimental accumulation of non-functional autophagosomes and autolysosomes. b | In the presence of initiation defects, stimulating autophagy upstream of autophagosome formation (in diseased cells) is expected to normalize autophagic flux (at least in part) and hence mediate beneficial effects, whereas boosting lysosomal degradation may exert limited (if any) therapeutic activity. c | In the presence of degradation defects, activating autophagy upstream of autophagosome formation (in diseased cells) may aggravate disease severity by exacerbating (thick arrows) the accumulation of non-functional autophagosomes and autolysosomes. Conversely, accelerating lysosomal degradation or inhibiting initiation (in diseased cells) may exert beneficial effects, at least to some degree (dashed arrow). d | Boosting autophagic flux in cells that survived a pathological insult or in non‐diseased cells may favour functional recovery and/or mediate beneficial effects linked to improved inflammatory tissue homeostasis. Beneficial and detrimental interventions are indicated by green and red arrows, respectively.