PIKfyve, a phosphoinositide 5 - kinase, is a key enzyme in eukaryotic cells. It binds to membrane phosphatidylinositol (PtdIns)3P and synthesizes PtdIns(3,5)P2 and PtdIns5P [4,5]. These signaling lipids are crucial for cellular homeostasis, membrane trafficking, and transcription [2]. PIKfyve exists in a multi - protein “PAS” complex with ArPIKfyve and Sac3, which relays signals for the synthesis and turnover of PtdIns(3,5)P2 [5].

Genetic and pharmacological studies in mouse models have shown significant implications of PIKfyve. In cancer, ablation of Pikfyve in CD11c+ cells enhanced the function of these cells, restrained tumor growth, and potentiated immune checkpoint blockade efficacy [3]. In ALS, pharmacological inhibition of PIKFYVE kinase activated an unconventional protein clearance mechanism, ameliorated ALS pathology, and extended survival in animal models and patient - derived motor neurons [1,6]. In pancreatic cancer, PIKfyve is overexpressed in cancer cells compared to normal cells, and its inhibition triggered a lipogenic gene expression program, creating a dependency on de novo lipid metabolism pathways, and showed synthetic lethality when combined with KRAS - MAPK - directed therapies [7].

In conclusion, PIKfyve plays essential roles in multiple biological processes, especially in membrane - related functions. Model - based research, such as KO/CKO mouse models, has revealed its significance in diseases like cancer, ALS, and pancreatic cancer. These studies provide potential therapeutic strategies by targeting PIKfyve in these disease areas.