Dietary nitrate and nitrite protect against doxorubicin-induced cardiac fibrosis and oxidative protein damage in tumor-bearing mice

Anthracycline-induced cardiotoxicity remains a major limitation in cancer therapy, affecting long-term cardiovascular health in survivors. Dietary nitrate supplementation has shown cardioprotective effects in preclinical models of doxorubicin (Dox)-induced and ischemia-reperfusion injury. In this study, we evaluated the protective effects of nitrate and nitrite (NOx) supplementation in a syngeneic, tumor-bearing mouse model undergoing Dox chemotherapy (N=5 per group). NOx supplementation significantly reduced cardiac fibrosis and levels of 4-hydroxynonenal-modified proteins, a marker of oxidative stress. Tumor sizes varied, but most regressed by the final Dox dose. Importantly, NOx did not compromise the anti-tumor efficacy of Dox nor did it promote pulmonary metastasis. These findings support the potential clinical use of dietary nitrate and nitrite as adjuncts to Dox treatment to mitigate cardiotoxicity without impairing anti-cancer outcomes. Graphical Abstract