Hydralazine as a Repurposed Epigenetic and Metabolic Modulator in Glioblastoma: Promise, Pitfalls, and Future Directions

Glioblastoma multiforme (GBM) remains one of the most challenging malignancies to treat, characterized by extreme heterogeneity, therapeutic resistance, and a dismal prognosis. Current multimodal treatments frequently fail due to the tumor’s complex epigenetic landscape, infiltrative nature, and a highly hypoxic microenvironment that fosters immune evasion. This review evaluates the potential of repurposing hydralazine, a long-established FDA-approved vasodilator, as a novel epigenetic and metabolic modulator for GBM. Mechanistically, hydralazine acts as a non-nucleoside inhibitor of DNA methyltransferase (DNMT), facilitating the demethylation and reactivation of silenced tumor suppressor genes, such as p16 and GSTP1. Beyond its epigenetic effects, it influences tumor metabolism by modulating the adenosine signaling axis and inducing vascular dynamics—specifically the “vascular steal” phenomenon—that alter intratumoral oxygenation. These pleiotropic actions provide a compelling rationale for its use in sensitizing glioblastoma cells to conventional radiotherapy and chemotherapy. However, significant pharmacological hurdles, including uncertain blood-brain barrier penetration, a short plasma half-life, and risks of systemic toxicity such as drug-induced lupus, suggest that hydralazine is unlikely to be effective as a stand-alone clinical therapy. In conclusion, while hydralazine faces clear translational pitfalls as a monotherapy, its ability to strategically reshape the GBM biological landscape positions it as a valuable adjunctive agent. Future innovation must focus on optimizing central nervous system delivery and identifying biology-driven combination strategies to overcome the adaptive resistance of this aggressive disease.