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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma with limited therapeutic options and a poor prognosis.
• Dihydrotanshinone I (DT), a compound from Danshen, has demonstrated anti-inflammatory and antitumor effects, but its impact on RMS is not well understood.

Purpose of the Study:

• To investigate the mechanism of cell death induced by Dihydrotanshinone I (DT) in rhabdomyosarcoma (RMS).
• To explore the potential of DT as a therapeutic agent for RMS by evaluating its anti-RMS efficacy and underlying molecular mechanisms.

Main Methods:

• Utilized various inhibitors to determine the mode of cell death induced by DT.
• Employed RNA sequencing and co-immunoprecipitation assays to elucidate the mechanism of DT-induced ferroptosis.
• Evaluated the anti-RMS efficacy of DT in vitro and in nude mouse xenograft models.

Main Results:

• DT was found to induce ferroptosis in RMS cells.
• DT triggers ferroptosis by inducing ubiquitination and degradation of HSP90AA1, which inhibits the HSP90AA1/RACK1/AKT signaling axis.
• DT significantly suppressed the proliferation of RMS in both experimental models.

Conclusions:

• DT effectively inhibits RMS proliferation by inducing ferroptosis through the degradation of HSP90AA1.
• DT shows potential as a therapeutic candidate for RMS.
• Targeting ferroptosis represents a promising strategy to improve treatment outcomes for RMS.