Nuclear phosphoinositide signaling in cell biology and disease

Phosphatidylinositol phosphates (PIPs), or phosphoinositides, are minor yet essential phospholipids that govern diverse cellular processes, from membrane trafficking to signal transduction. While traditionally studied within the cell membranes, emerging evidence reveals their dynamic metabolism and critical functions in the nucleus, particularly within the non-membrane nucleoplasm, continually reshaping our understanding of the nuclear PIP-lipidome and its therapeutic potential. However, an updated overview of the nuclear PIP landscape and its selective modulators remains lacking. This review addresses this gap by providing an integrated summary of nuclear PIP signaling components, encompassing their structures, species, distribution, transport, and metabolic regulation. A focus is placed on pharmacological modulation, including inhibitors and activators targeting nuclear phosphatidylinositol (PI/PtdIns) transfer proteins and PIP-metabolizing enzymes, with attention to structure-based inhibitor classes and representative clinical-stage compounds. We conclude by outlining therapeutic opportunities that arise from targeting the nuclear PIP pathway, particularly in the context of cancer, cardiovascular disease, and neurodegeneration. In this review, Chen et al. discuss how phosphoinositides function as spatially confined protein-centric signaling molecules within the nucleus, governed by principles distinct from membrane-delimited lipid signaling. They integrate emerging conceptual frameworks with a systematic analysis of inhibitors and activators targeting nuclear PIP metabolic enzymes and lipid transfer pathways.