Loughran, R. M. | Search bioRxiv

bioRxiv2025

PI5P4Kα Regulates Iron Balance to Promote Metabolic Fitness in Pancreatic Cancer

Phosphoinositide kinases generate distinct phosphoinositides that regulate processes that maintain cellular fitness. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) have garnered interest for their role in cancer metabolism and cellular trafficking; however, their function in pancreatic ductal adenocarcinoma (PDAC) remains unexplored. Given the unique metabolic demands of PDAC cells, which heavily rely on altered trafficking pathways to support their growth, investigating PI5P4Ks in this context may reveal critical insights. We identify PI5P4K as a regulator of PDAC cell fitness through its key role in maintaining iron homeostasis. PI5P4K depletion causes metabolic disruptions and reduced intracellular iron import, leading to the induction of apoptosis in PDAC cells that is reversed by iron supplementation. Notably, we find that PI5P4K knockdown suppresses tumor growth in a xenograft mouse model of PDAC. These results not only illuminate the mechanistic underpinnings of PI5P4K function in PDAC but also position it as a promising therapeutic target for this disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/647654v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@17f52e5org.highwire.dtl.DTLVardef@1b78c1org.highwire.dtl.DTLVardef@194e09aorg.highwire.dtl.DTLVardef@125b3c9_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic representation of the novel function and implication of PI5P4K in PDAC. PI5P4K is upregulated in PDAC to support the ferro-addiction and heightened metabolic requirements of the tumor. When PI5P4K is inhibited, the PDAC cells undergo apoptotic cell death due to iron depletion. PI5P4K-depleted PDAC cells upregulate autophagy as an adaptive response but is not sufficient to defend against apoptotic cell death.

cancer biology↗

bioRxiv2025

Noncanonical PI(4,5)P2 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)P2 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.

cell biology↗