Vericiguat protects against doxorubicin-induced myocardial injury by modulating glycolysis and histone lactylation through RELB regulation

Doxorubicin (DOX) is a widely used chemotherapeutic agent whose clinical utility is restricted by cumulative cardiotoxicity. Vericiguat, a soluble guanylate cyclase stimulator approved for the treatment of heart failure, has shown cardioprotective potential; however, the underlying metabolic and epigenetic mechanisms that contribute to its protective effects against DOX-induced myocardial injury remain unclear. The treatment suppressed the expression of key glycolytic enzymes, including HK2, PKM, LDHA, and LDHB, reduced lactate accumulation, and reversed increased histone lactylation at multiple sites. Integrated Cut&Tag and RNA-seq analyses identified RELB as a histone lactylation-associated gene suppressed by Vericiguat. Functional assays demonstrated that overexpression of RELB diminished the protective effects of Vericiguat, reinstating glycolytic activation, histone lactylation, and inflammatory responses. Conversely, RELB knockdown mimicked the protective effects of Vericiguat and largely eliminated the additional effects of Vericiguat on glycolysis, histone lactylation, inflammation, oxidative stress, cell viability, and apoptosis. In vivo, Vericiguat improved myocardial morphology and alleviated apoptosis and inflammation in DOX-treated mice. These findings demonstrate that Vericiguat mitigates doxorubicin-induced myocardial injury through metabolic-epigenetic regulation involving glycolysis, histone lactylation, and RELB, suggesting a potential therapeutic strategy for anthracycline-induced cardiotoxicity.