Repurposing statins for choriocarcinoma: targeting the mevalonate pathway to disrupt mechanosignaling and overcome therapeutic resistance.

Choriocarcinoma is a rare but highly aggressive gestational trophoblastic tumor, characterized by early vascular invasion and distant metastasis. While cure rates exceed 90% with chemotherapy, patients with high-risk, bulky, or chemoresistant disease have a poor prognosis. This review explores the repurposing of statins as a novel therapeutic strategy, hypothesizing that their inhibition of the mevalonate pathway critically disrupts the mechanosignaling networks that drive choriocarcinoma invasion and resistance. By depleting geranylgeranyl pyrophosphate (GGPP), statins inactivate Rho family GTPases, master regulators of cytoskeletal dynamics and cellular mechanics. In choriocarcinoma models, this step leads to the collapse of the actin cytoskeleton, abrogation of cell migration, and suppression of matrix metalloproteinase activity. Preclinical studies demonstrate that achievable concentrations of simvastatin and atorvastatin reduce proliferation, trigger apoptosis, lower β-hCG secretion, and inhibit tumor growth and metastasis, even in chemoresistant lines. GGPP, but not cholesterol, reverses these effects, confirming a prenylation-dependent mechanism. To build a translational rationale, we synthesize the epidemiology, risk factors, and pathophysiology of choriocarcinoma with statin pharmacology. The evidence suggests that statins attack a core vulnerability of this malignancy by impairing mechanotransduction, effectively reprogramming the tumor cell from an invasive to a static state. We argue for early-phase clinical trials of statins in high-risk or refractory choriocarcinoma, positioning them as a promising, low-toxicity adjunct that targets the biomechanical engines of disease progression.