Fig. 3: Lysosomal damage and cell fate.

Apoptosis appears to be triggered by lysosomal damage in a mitochondria-dependent manner. Cathepsins are released from damaged lysosomes and cleave BID into tBid, in turn promoting the oligomorphism of BAX, which can be further enhanced by cathepsin-induced degradation of Bcl-2. Then, BAX is transferred to the mitochondrial outer membrane, causing excessive formation of the MPTP. Through the MPTP, cyto C is released into the cytoplasm and promotes the formation of apoptosomes, further inducing apoptosis. Necroptosis is stimulated by the inhibition of lysosomal function, resulting in significant accumulation of necrosome components (RIPK1 and RIPK3) and hydrolyzed caspase-8 by the release of cathepsin D. Necroptosis executor (MLKL) is phosphorylated by necrosomes and translocated to the cell membrane or organelle membrane, thereby leading to necroptosis. Pyroptosis is induced by damaged lysosomes through the cleavage of GSDMD into GSDMD-N by the release of cathepsin G, and activating NLRP3 and caspase-1 by the release of cathepsin B. Subsequently, pyroptosis leads to cell perforation and the massive release of IL-1β and IL-18. Additionally, ferroptosis can be exacerbated by the release of ROS produced by Fe²⁺ and H₂O₂ from damaged lysosomes.