Lysosomes are degradation and signaling centers within the cell,and their dysfunction impairs a wide variety of cellular processes,To understand the cellular effect of lysosome damage,we screened natural small-molecule compounds that induce lysosomal abnormal-Ity using Caenorhabditis elegans (C.elegans) as a model system.A group of vobasinyl-ibogan type bisindole alkaloids (ervachinines A-D) were identified that caused lysosome enlargement In C.elegans macrophage-like cells.Intriguingly,these compounds triggered call death in the germ line independently of the canonical apoptosls pathway.In mammalian cells,ervachinines A-D induced lysosomal enlargement and damage,leading to leakage of cathepsin proteases,inhibition of autophagosome degradation and necrotic cell death.Further analysis revealed that this ervachinine-induced lysosome damage and lysosomal cell death depended on STAT3 signaling,but not RIP1 or RIP3 signaling.These findings suggest that lysosome-damaging compounds are promising reagents for dissecting signaling mechanisms underlying lysosome homeostasis and lysosome-related human disorders.