Activation of Lysosomal Retrograde Transport Triggers TPC1‐IP3R1 Ca2+ Crosstalk at Lysosome‐ER MCSs Leading to Lethal Depleting of ER Calcium

Abstract Inter‐organellar signaling linkages in oncology are increasingly elucidated. However, the impact of lysosome‐endoplasmic reticulum (ER) interaction on tumor cell fate remains relatively unexplored. A novel interaction between lysosomes and the ER, mediated by the flavonoid LW‐213 through targeting LIMP2 (lysosomal integral membrane protein type 2)to activate a lysosomal repair pathway, is identified in acute myeloid leukemia (AML). This leads to activated RAB7A activity, enhancing lysosomal retrograde transport to the perinuclear region and increasing contact at lysosome‐ER membrane contact sites (MCSs). Close proximity of TPC1 to IP3R1 at these sites generates a concentrated calcium microdomain, triggering Ca 2+ ‐induced Ca 2+ release, which causes cytoplasmic calcium turbulence and two distinct calcium tides. This excessive calcium efflux depletes ER calcium stores, triggering lethal ER stress‐induced apoptosis. Interestingly, altering TPC1 expression levels in HeLa cells affected these calcium dynamics, replicating AML‐specific mechanisms when overexpressed. Subsequent studies using BALB/c xenograft models with wild‐type and LIMP2‐knockout THP1 cells, along with ICR mice toxicity models, confirmed LW‐213′s significant tumor growth inhibition with minimal toxicity. These findings underscore the potential of targeting lysosomal‐ER calcium crosstalk as an innovative approach to cancer treatment, highlighting the therapeutic promise of LW‐213 in managing tumor cell fate through modulating organellar interactions.