Phosphatidylinositol 4‐kinase as a target of pathogens—friend or foe?

Phosphatidylinositol 4-kinases (PI4Ks) are pivotal enzymes responsible for the generation of phosphatidylinositol 4-phosphate (PI4P), a key precursor involved in various cellular signalling pathways that regulate vesicular trafficking, Golgi maintenance and intracellular communication. Conserved across eukaryotic species, PI4Ks exist in distinct isoforms with specific localisations and functions, ranging from plasma membrane dynamics to endosomal trafficking and autophagy regulation. Notably, numerous pathogens, including viruses, bacteria and parasites, have evolved mechanisms to hijack host PI4Ks, thereby facilitating intracellular replication and survival. For example, RNA viruses within the Flaviviridae and Coronaviridae families recruit PI4Ks to remodel host membranes for the assembly of replication complexes. Similarly, intracellular bacteria such as Salmonella and Legionella manipulate PI4P-enriched compartments to evade host defences and promote replication. Due to their central roles in both normal cellular physiology and infection, PI4Ks have emerged as promising therapeutic targets. A variety of inhibitors, including ATP-competitive compounds, have been developed and evaluated for their antiviral, antibacterial and antiparasitic potential. Nevertheless, challenges related to selectivity and toxicity remain. Recent advances include the identification of inhibitors effective against Plasmodium species and the development of compounds targeting PI4KIIIβ in infections with viruses such as hepatitis C and coronaviruses. This review highlights the dual role of PI4Ks as essential cellular regulators and exploitable pathogen cofactors, underscoring their potential as drug targets. Continued investigation into the structure, function and inhibition of PI4Ks may enable the development of selective therapeutic strategies for infectious diseases while minimising off-target effects on host cells.