The integrity of lysosomes is of vital importance to survival of tumor ceils.We demonstrated that LW-218,a synthetic flavonoid,induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy.LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D,as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents,which can alter the activity of cathepsins.Lysophagy,was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB.LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator.Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy.LW-218-induced enlargement and damage of lysosomes were triggered by abnormal choles-terol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracel-lular cholesterol transporter 1.Moreover,LW-218 inhibited the leukemia cell growth in vivo.Thus,the necessary impact of integral lysosomal function in cell rescue and death were illustrated.