Short-course sodium valproate — an anticonvulsant repurposed as a cardioprotective agent — administered at 15 mg/kg/day for ≤14 days before cardiac surgery reduced post-operative myocardial injury in a 42-participant randomized dose-finding trial. Single-nucleus multi-omics of myocardial biopsies revealed activation of hormetic p53 and Akt-GSK-3β ferroptosis protection pathways as the likely mechanism, independent of chromatin remodeling. Critically, longer or higher dosing (25 mg/kg/day or >14 days) reversed this benefit, producing a heart failure phenotype with suppressed ferroptosis defenses, endothelial-mesenchymal transition, and greater myocardial injury.
This finding sits at the intersection of two fast-moving fields: ferroptosis biology in cardiac ischemia-reperfusion injury, and drug repurposing for surgical cardioprotection. The identification of a narrow therapeutic window — where the same drug protects briefly but harms chronically — is mechanistically important and reinforces the hormesis principle increasingly recognized in longevity science. However, with only 42 participants and 38% non-compliance in higher-dose arms, the effect sizes remain preliminary. The as-treated (rather than intention-to-treat) troponin analysis adds confounding risk. This is a dose-finding, not an efficacy, trial; a powered phase II is required before clinical translation. Being a preprint not yet peer-reviewed, the multi-omics interpretations in particular warrant independent scrutiny. If confirmed, short-course valproate could offer a low-cost, accessible perioperative cardioprotection strategy for the millions undergoing cardiac surgery annually.
