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April 13th, 2025
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Sanford Burnham Prebys
cancer biology
biorxiv

PI5P4Kα Regulates Iron Balance to Promote Metabolic Fitness in Pancreatic Cancer

Arora, G. K.Open in Google Scholar•Loughran, R. M.Open in Google Scholar•Ly, K.Open in Google Scholar•Galapate, C. M.Open in Google Scholar•Llorente, A.Open in Google Scholar•Anderson, T. R.Open in Google Scholar•Scott, D. A.Open in Google Scholar•Altman, Y.Open in Google Scholar•Murad, R.Open in Google Scholar•Commisso, C.Open in Google Scholaret al.

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.

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