5-Oxoproline Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Doxorubicin (DOX), a classical chemotherapeutic agent, faces significant limitations because of its well-documented risk of inducing cardiotoxicity. Effective prevention of DOX-induced cardiotoxicity is urgently needed. Given that alterations in metabolic pathways have been observed in both cardiovascular diseases and cancer, targeting specific metabolic pathways may offer dual benefits by mitigating DOX-induced cardiotoxicity while simultaneously enhancing its antitumor efficacy. This study sought to explore the characteristic metabolic alterations associated with early DOX-induced cardiotoxicity and identify a therapeutic target that simultaneously inhibits cancer and protects the myocardium. Metabolomic and transcriptomic analyses were performed on heart tissues from murine models of DOX-induced cardiotoxicity to identify the most significantly altered metabolic pathway. The most altered metabolite involved in the candidate pathway was chosen and verified in both mice and humans. The protective effects of the chosen metabolite against DOX-induced cardiotoxicity and its antitumor effects were evaluated. Potential mechanisms were explored using C57BL/6J mice, OPLAH global knockout mice, BALB/c nude mice and NSG mice. The glutathione metabolic pathway was identified as the most altered pathway in heart tissues with DOX-induced cardiotoxicity. The 5-oxoproline/OPLAH (5-oxoprolinase) axis was the most critical node. Downregulation of 5-oxoproline was observed in serum samples from both humans and mice. Exogenous 5-oxoproline supplementation effectively restored myocardial 5-oxoproline levels, subsequently mitigating DOX-induced cardiac dysfunction. Interestingly, we observed an additional inhibitory effect of 5-oxoproline on tumor proliferation in tumor-bearing mice treated with DOX. Mechanistically, 5-oxoproline exerts its cardioprotective effects by restoring glutathione metabolic homeostasis through the modulation of its downstream enzyme OPLAH while simultaneously suppressing tumor proliferation by inhibiting its upstream enzyme, gamma-glutamyl cyclotransferase (GGCT). This study reveals a previously unrecognized dual role of 5-oxoproline, which functions both as an early biomarker for DOX-induced cardiotoxicity detection and as a therapeutic target that simultaneously inhibits cancer growth and protects the myocardium.