Dihydrotanshinone I as a novel signal transducer and activator of transcription 3 inhibitor for glioblastoma treatment

Background Among tumors affecting the central nervous system (CNS), glioblastoma multiforme (GBM) is the most aggressive and lethal form. Given the complex mechanisms of the CNS and the blood-brain barrier (BBB), effective therapies for GBM remain limited. To identify potential therapeutic candidates for glioma, we developed a small-molecule library to screen for compounds with potent anti-proliferative effects and BBB permeability. The mechanisms underlying their anti-glioma activity were further elucidated to provide insights into new treatment strategies. Methods A library of small molecules was screened to identify agents that significantly inhibit glioma cells activity. The effects of the lead compound (Dihydrotanshinone I, DHT) on glioma progression were evaluated through a series of experimental approaches, including cell counting kit-8 assays, cell cycle analysis, apoptosis detection, wound healing, transwell migration, reactive oxygen measurement, subcutaneous xenograft mouse models, and intracranial orthotopic tumor models. To elucidate the underlying mechanisms, network pharmacology and transcriptomic analyses were employed. The mechanism of DHT in glioma pathogenesis was further validated using bioinformatics analyses and clinical glioma tissue samples. Results Based on pharmacokinetic evaluation, DHT was found to traverse the BBB, indicating its capacity to reach the cerebral parench. In vitro and in vivo experiments demonstrated that DHT significantly suppresses glioma growth and progression. Mechanistic analyses using network pharmacology and RNA sequencing revealed that DHT induces glioma cell apoptosis by inhibiting the Janus kinase-signal transducer and activator of transcription 3 (STAT3) signaling pathway, increasing intracellular reactive oxygen species levels and triggering intrinsic apoptotic cascades. Furthermore, bioinformatic analyses of clinical cohorts coupled with validation in patient-derived glioma specimens confirmed that elevated STAT3 expression was correlated with unfavorable prognosis and was significantly increased in patients with high-grade glioma. Conclusions This study demonstrates that, in addition to its role as a key contributor to glioma malignancy and a prognostic marker, STAT3 is also a target of DHT, highlighting its potential as a promising therapeutic candidate for treating GBM. Graphical