Tanshinone IIA promotes ferroptosis in cutaneous melanoma via STAT1-mediated upregulation of PTGS2 expression

BACKGROUND: Melanoma is highly aggressive, metastatic with a poor prognosis. Despite significant advances in targeted therapies and immunotherapies, their efficiency limited by drug resistance. Tanshinone IIA (Tan IIA), a bioactive compound derived from Traditional Chinese plant, exhibits significant anticancer potential, which still needs more research in its complex regulatory mechanisms. PURPOSE: This study aimed to elucidate the putative targets and regulatory mechanisms of Tan IIA in anti-melanoma, with a focus on its role in inducing ferroptosis. STUDY DESIGN: We designed the experiment to explore the effects of Tan IIA on melanoma through both in vitro and in vivo experiments and to investigate the underlying mechanisms through transcriptomics combining network pharmacology analysis. METHOD: , reactive oxygen species (ROS) and glutathione (GSH) in vivo and in vitro. RNA sequence was performed to explore the key regulatory pathways involved in Tan IIA-induced ferroptosis. Chromatin immunoprecipitation (ChIP) and Luciferase assays were used to validate transcription factor responsible for prostaglandin-endoperoxide synthase 2 (PTGS2) regulation. Additionally, RT-qPCR, western blot, IF, IHC were aimed to evaluate the expression of target gene. RESULT: Tan IIA markedly suppresses melanoma growth in a xenograft model. The same effect performed on inhibition melanoma cells and promotion to ferroptosis with accumulation of ROS, MDA, and Fe²⁺levels and GSH consumption. RNA sequencing and public database analysis revealed that Tan IIA regulates PTGS2, the critical marker of ferroptosis, and PTGS2-knockdown attenuates Tan IIA -induced ferroptosis in melanoma cells. Furthermore, we identified that Tan IIA stimulate signal transducer and activator of transcription 1 (STAT1), a transcription factor, promoting PTGS2 expression and localized in the cell cytoplasm. Moreover, downregulation of the transcription factor STAT1 lead to PTGS2 downregulation and also inhibit ferroptosis in melanoma. CONCLUSION: This study, the first to link Tan IIA-induced ferroptosis to the STAT1/PTGS2 axis in melanoma, identifies STAT1 and PTGS2 as novel therapeutic targets for melanoma, which demonstrates the potential of natural compounds Tan IIA in overcoming drug resistance and integrates traditional medicine with advanced molecular techniques for mechanistic exploration.