Abstract: Provided are methods for treating and/or preventing genotoxic stress-induced cardiac toxicity, which in some embodiments include administering to a subject an effective amount of an inhibitor of t-CH, of neutrophil activation, of neutrophil migration, or any combination thereof. In some embodiments, the genotoxic stress-induced cardiac toxicity results from exposure to one or more anti-tumor and/or anti-cancer therapies, including but not limited to treatment with one or more chemotherapeutics (e.g., doxorubicin) and/or treatment with radiation. In some embodiments, the genotoxic stress-induced cardiac toxicity, the chemotherapy-induced cardiac toxicity, the chemotherapy-induced heart damage, and/or the chemotherapy-induced reduction in cardiac function is characterized by a reduction in cardiac contractility, a thinning of a ventricular wall, a reduction in cardiomyocyte size, or any combination thereof.

Abstract: As demonstrated herein, a preferential and progressive expansion of a subset of hematopoietic cells bearing somatic mutations in one or more HSC cardiometabolic driver genes leads to pro-inflammatory signaling at multiple levels. Accordingly, provided herein are compositions, methods, and assays for modulating a HSC cardiometabolic driver gene mutation-mediated proinflammatory activity.