Noncanonical PI(4,5)P coordinates lysosome positioning through cholesterol trafficking.

In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 (SREBP-2) pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, new strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport. In this study, we investigate a previously underexplored function of PI5P4Ks, which catalyzes the conversion of PI(5)P to PI(4,5)P at intracellular membranes. Our findings reveal that PI5P4Ks play a key role in facilitating lysosomal cholesterol transport, regulating lysosome positioning, and sustaining growth signaling via the mTOR pathway. While PI5P4Ks have previously been implicated in mTOR signaling and tumor proliferation in p53-deficient contexts, this work elucidates an upstream mechanism that unifies these earlier observations.