Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Taxifolin promotes glioma stem cell differentiation via CYP1B1-mediated EMT suppression.
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Li Mengxin, Yang Jiaying, Wang Keyan, Zhu Aonan, Yin Haoyuan, Li Zongjun, Zhao Haoran, Wang Qi, Kalvakolanu Dhan V, Hao Yuewen, Cui Bing, Zhang Ling, Guo Baofen
Аннотация
BACKGROUND: Glioblastoma (GBM) progresses aggressively and resists therapy largely due to glioma stem cells (GSCs), which drive recurrence and treatment failure. Inducing GSC differentiation into non-stem-like cells offers a promising therapeutic approach. Taxifolin (TAX), a natural flavonoid with anti-inflammatory and antioxidant properties, has demonstrated anti-stemness effects in cancer but its impact on GSCs remains unclear.
PURPOSE: The study aimed to explore TAX as a differentiation-inducing agent targeting GSCs to enhance therapeutic response in GBM.
STUDY DESIGN: We assessed the effects and mechanism of TAX on GSC proliferation, self-renewal, and differentiation using in vitro and in vivo models, supported by transcriptomic and rescue experiments.
METHODS: Using human (TS576) and murine (CSC2078) GSC lines, along with an orthotopic xenograft model, we examined the effects of TAX on proliferation, self-renewal, and differentiation, as well as its downstream pathway. Funcional assays including cell viability, colony formation, neurosphere formation, apoptosis, and differentiation marker analysis were conducted in vitro. Transcriptomic profiling and KEGG pathway enrichment identified CYP1B1 as a key downstream target, whose role was validated through overexpression-based rescue experiments and epithelial-mesenchymal transition (EMT) marker analysis. TAX efficacy and biosafety were evaluated using bioluminescence imaging, histopathology and immunohistochemistry in vivo, with temozolomide as a positive control.
RESULTS: Purified TAX (92.47%) from Larix olgensis roots inhibited the proliferation, self-renewal of GSCs and induced apoptosis. TAX promoted GSCs differentiation toward neuronal lineages, supporting its potential as a differentiation-based adjuvant therapy. TAX suppressed tumor growth without observable toxicity and enhanced the therapeutic efficacy of temozolomide (TMZ) in vivo. Bioinformatic analysis identified CYP1B1 as a TAX-responsive target, with elevated expression in glioma tissues and strong association with malignancy and poor prognosis. Functional assays confirmed that CYP1B1 overexpression promotes EMT, while TAX downregulates CYP1B1 and inhibits EMT progression.
CONCLUSION: This study is the first to demonstrate that TAX promotes neuronal differentiation of GSCs by suppressing the CYP1B1-mediated EMT pathway. Our work uncovers a novel mechanism linking CYP1B1 down-regulation to GSC differentiation. These findings establish TAX as a differentiation-inducing agent and propose a new therapeutic strategy for GBM by targeting stemness and EMT concurrently.
PURPOSE: The study aimed to explore TAX as a differentiation-inducing agent targeting GSCs to enhance therapeutic response in GBM.
STUDY DESIGN: We assessed the effects and mechanism of TAX on GSC proliferation, self-renewal, and differentiation using in vitro and in vivo models, supported by transcriptomic and rescue experiments.
METHODS: Using human (TS576) and murine (CSC2078) GSC lines, along with an orthotopic xenograft model, we examined the effects of TAX on proliferation, self-renewal, and differentiation, as well as its downstream pathway. Funcional assays including cell viability, colony formation, neurosphere formation, apoptosis, and differentiation marker analysis were conducted in vitro. Transcriptomic profiling and KEGG pathway enrichment identified CYP1B1 as a key downstream target, whose role was validated through overexpression-based rescue experiments and epithelial-mesenchymal transition (EMT) marker analysis. TAX efficacy and biosafety were evaluated using bioluminescence imaging, histopathology and immunohistochemistry in vivo, with temozolomide as a positive control.
RESULTS: Purified TAX (92.47%) from Larix olgensis roots inhibited the proliferation, self-renewal of GSCs and induced apoptosis. TAX promoted GSCs differentiation toward neuronal lineages, supporting its potential as a differentiation-based adjuvant therapy. TAX suppressed tumor growth without observable toxicity and enhanced the therapeutic efficacy of temozolomide (TMZ) in vivo. Bioinformatic analysis identified CYP1B1 as a TAX-responsive target, with elevated expression in glioma tissues and strong association with malignancy and poor prognosis. Functional assays confirmed that CYP1B1 overexpression promotes EMT, while TAX downregulates CYP1B1 and inhibits EMT progression.
CONCLUSION: This study is the first to demonstrate that TAX promotes neuronal differentiation of GSCs by suppressing the CYP1B1-mediated EMT pathway. Our work uncovers a novel mechanism linking CYP1B1 down-regulation to GSC differentiation. These findings establish TAX as a differentiation-inducing agent and propose a new therapeutic strategy for GBM by targeting stemness and EMT concurrently.