Target practice: Opportunities for therapeutic intervention in CHIP and CCUS

Clonal hematopoiesis (CH) is defined by the expansion of hematopoietic stem and progenitor cells (HSPCs) harboring somatic mutations that confer a competitive advantage. Clonal cytopenia of undetermined significance (CCUS), a subtype of CH characterized by cytopenias, represents a high-risk precursor to myeloid malignancies and is increasingly associated with cardiovascular disease, thrombosis, and chronic inflammatory conditions. Despite its clinical significance, therapeutic strategies for CCUS remain limited, and prospective trial frameworks are still evolving. In this review, we outline emerging therapeutic opportunities in CCUS, including inflammatory targets (e.g., NLRP3, IL-1β, IL-6), epigenetic modulators (e.g., hypomethylating agents, Vitamin C), mutation-specific inhibitors (e.g., JAK2, IDH1/2), and repurposed agents (e.g., statins, metformin, colchicine). We also discuss key elements of early-phase clinical trial design, such as risk stratification, endpoint selection, and ethical enrollment of at-risk individuals. CCUS offers a unique window for preventive intervention before the onset of overt malignancy or irreversible end-organ damage. Realizing this potential will require translating biologic insights into well-designed randomized clinical trials that incorporate careful patient selection, ethical enrollment practices, and clinically relevant endpoints. Establishing such frameworks will be essential to developing effective, targeted strategies in this high-risk population.