Integrated Multiomic Analysis Reveals the Therapeutic Potential of Danhong Injection in Mitigating Radiation‐Induced Heart Disease by Modulating Ferroptosis

Radiation-induced heart disease (RIHD) has garnered increasing clinical attention. While oxidative stress plays a pivotal role in RIHD pathogenesis and progression, the involvement of ferroptosis-a regulated cell death pathway closely linked to oxidative stress-remains poorly characterized. Danhong injection (DHI), a clinically approved traditional Chinese medicine, is widely used for treating cardiovascular disorders because of its anti-inflammatory and antioxidant properties. Therefore, we investigated whether DHI exerts therapeutic effects against RIHD by suppressing ferroptosis. We established both in vivo and in vitro RIHD models. Ferrostatin-1 (Fer-1), a selective ferroptosis inhibitor, was used as a positive control. Mice and cardiomyocytes (H9C2 and AC16 cell lines) were treated with DHI postirradiation. Myocardial tissue/cellular/mitochondrial damage was comprehensively assessed through histopathological and functional analyses. Oxidative/antioxidant imbalance was quantified via biochemical assays, and ferroptosis-related protein expression was evaluated using immunohistochemistry and Western blotting. Finally, transcriptomic and metabolomic sequencing, coupled with bioinformatics approaches, was performed using murine myocardial tissues to elucidate molecular alterations. X-irradiation induced structural and functional damage in myocardial tissues and cells, accompanied by oxidative stress and ferroptosis activation. DHI treatment significantly mitigated those effects, restoring myocardial integrity and viability. Differentially expressed genes and metabolites were predominantly enriched in immune response pathways and metabolic reprogramming processes. Promising RNA-metabolite interactions that may serve as therapeutic targets for future investigations were revealed. DHI ameliorates RIHD by inhibiting ferroptosis. Integrated multiomics not only validated the therapeutic potential of DHI but also provided novel insights into the molecular mechanisms underlying radiation-induced cardiac injury.