Dihydrotanshinone I Induces Ferroptosis in Rhabdomyosarcoma by Targeting HSP90AA1/RACK1/AKT Axis

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma with limited treatment options and poor prognosis. Dihydrotanshinone I (DT), a bioactive compound from Danshen, exhibits anti-inflammatory and antitumor properties, but its effects on RMS remain unclear. To investigate the mode of cell death induced by DT, various inhibitors were employed. RNA sequencing and co-immunoprecipitation assays were utilized to explore the mechanism of DT-induced ferroptosis in RMS. Furthermore, the anti-RMS efficacy of DT was evaluated through in vitro experimental models and nude mouse xenograft models. We found that DT induces the ubiquitination and degradation of HSP90AA1, thereby inhibiting the HSP90AA1/RACK1/AKT signaling axis and subsequently triggering ferroptosis in RMS. This process significantly suppresses the proliferation of RMS. These findings highlight the potential of DT as a therapeutic candidate for RMS and propose a ferroptosis-targeting strategy that may improve treatment outcomes.