Targeting HSP90 destabilization with ganoderic acid a as a novel therapeutic strategy for hepatoblastoma.
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BACKGROUND: Hepatoblastoma (HB) is the most prevalent primary liver malignancy in children and is characterized by aggressive progression and suboptimal therapeutic outcomes. Despite advances in multimodal treatment strategies, the prognosis of high-risk or relapsed HB remains poor, highlighting an urgent need for novel and effective therapeutic approaches. Ganoderic acid A (GAA), a bioactive triterpenoid derived from Ganoderma lucidum, has demonstrated antitumor activity across multiple cancer types; however, its therapeutic potential and mechanistic role in HB have not yet been elucidated. METHODS: A comprehensive experimental framework integrating in vitro functional assays, in vivo xenograft models, and mechanistic investigations was employed to evaluate the antitumor effects of GAA in HB. Cellular proliferation, migration, apoptosis and senescence were systematically assessed. In vivo therapeutic efficacy was determined using bioluminescence imaging in xenograft models. Molecular docking, molecular dynamics simulations and genetic overexpression analyses were conducted to elucidate the molecular targets and mechanistic basis of GAA action. RESULTS: GAA exerted significant antitumor effects in HB cells by markedly inhibiting proliferation, migration and invasion, while simultaneously inducing apoptosis and cellular senescence. In vivo, GAA treatment resulted in a substantial reduction in tumor burden in HB xenograft models. Mechanistic studies revealed that GAA directly interacts with heat shock protein 90 alpha family class A member 1 (HSP90), leading to impairment of its chaperone function and promoting proteasome-mediated degradation. Importantly, enforced overexpression of HSP90 effectively attenuated the antitumor effects of GAA, establishing HSP90 as a critical functional mediator. Molecular dynamics simulations further substantiated the stable binding and atomic-level interactions between GAA and HSP90. CONCLUSIONS: This study identifies GAA as a previously unrecognized senescence-inducing agent in HB through targeted degradation of HSP90, thereby revealing a novel therapeutic vulnerability. Collectively, these findings position GAA as a promising candidate for targeted therapy in HB and provide a strong rationale for its further translational development.