PIKfyve, a phosphoinositide 5-kinase, belongs to an evolutionarily ancient gene family. It synthesizes PtdIns(3,5)P₂ and PtdIns5P in cells, and is a key component in a protein complex with Fig4 and Vac14 that tightly regulates the levels of PI(3,5)P₂ and PI(5)P. These phosphoinositides play critical roles in cellular homeostasis, membrane trafficking, and transcription [2,5,7].

In ALS models, pharmacological inhibition of PIKFYVE kinase activates an unconventional protein clearance mechanism, which ameliorates ALS pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of ALS [1,6]. In cancer, genetic and pharmacological studies show that PIKfyve ablation enhances the function of CD11c⁺ cells, restraining tumor growth, enhancing DC-dependent T cell immunity, and potentiating immune checkpoint blockade (ICB) efficacy in tumor-bearing mouse models. PIKfyve inhibitors also cause cytoplasmic vacuolation and non-apoptotic death in cancer cells, with one inhibitor, apilimod, already in clinical trials for B-cell malignancies. Additionally, in pancreatic cancer, PIKfyve is overexpressed, and its inhibition obligates the cancer to upregulate de novo lipid synthesis, and simultaneous targeting of PIKfyve and KRAS-MAPK leads to tumor elimination or regression [3,4,8].

In conclusion, PIKfyve is essential for regulating phosphoinositide levels involved in crucial cellular processes. Studies using genetic and pharmacological manipulations, including gene knockout-like effects in animal models, have revealed its significance in neurodegenerative diseases like ALS and in various cancers. These findings offer potential therapeutic strategies for these diseases by targeting PIKfyve [1,3,4,6,8].