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Baicalin induces ferroptosis in osteosarcomas through a novel Nrf2/xCT/GPX4 regulatory axis
Rui-Jia Wen1, Xin Dong2, Hao-Wen Zhuang3
1Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, P.R. China; Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518000, P.R. China.
Background:
Osteosarcomas (OS) is a kind of malignant bone tumor which occurs primarily in children and adolescents, and the clinical therapeutics remain disappointing. As a new programmed cell death, ferroptosis is characterized by iron dependent and intracellular oxidative accumulation, which provides a potential alternative intervene for the OS treatment. Baicalin, a major bioactive flavone derived from traditional Chinese medicine Scutellaria baicalensis, has been proved to have anti-tumor properties in OS. Whether ferroptosis participated in the baicalin mediated anti-OS activity is an interesting project.
Purpose:
To explore the pro-ferroptosis effect and mechanisms of baicalin in OS.
Methods/Study Design:
Pro-ferroptosis effect of baicalin on cell death, cell proliferation, iron accumulation, lipid peroxidation production was determined in MG63 and 143B cells. The levels of glutathione (GSH), oxidized (GSSG) glutathione and malondialdehyde (MDA) were determined by enzyme linked immunosorbent assay (ELISA). The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Glutathione peroxidase 4 (GPX4) and xCT were detected by western blot in baicalin-mediated ferroptosis regulation. In vivo, a xenograft mice model was adopted to explore the anticancer effect of baicalin.
Results:
In the present study, it was found that baicalin significantly suppress tumor cell growth in vitro and in vivo. By promoting the Fe accumulation, ROS formation, MDA production and suppressing the ratio of GSH/GSSG, baicalin was found to trigger ferroptosis in OS and ferroptosis inhibitor ferrostatin-1 (Fer-1) successfully reversed these suppressive effects, indicating that ferroptosis participated in the baicalin mediated anti-OS activity. Mechanistically, baicalin physically interacted with Nrf2, a critical regulator of ferroptosis, and influenced its stability via inducing ubiquitin degradation, which suppressed the Nrf2 downstream targets GPX4 and xCT expression, and led to stimulating ferroptosis.
Conclusions:
Our findings for the first time indicated that baicalin exerted anti-OS activity through a novel Nrf2/xCT/GPX4-dependent ferroptosis regulatory axis, which hopefully provides a promising candidate for OS treatment.
Insights
Baicalin, a natural compound, effectively treats osteosarcoma (OS) by inducing ferroptosis, a programmed cell death pathway. It targets the Nrf2/xCT/GPX4 axis, offering a promising new therapeutic strategy for OS.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Osteosarcoma (OS) is a prevalent bone cancer in children and adolescents with limited treatment options.
- Ferroptosis, an iron-dependent cell death, presents a novel therapeutic avenue for OS.
- Baicalin, a natural flavone from Scutellaria baicalensis, exhibits anti-tumor effects in OS.
Purpose of the Study:
- To investigate the ferroptosis-inducing effects of baicalin in osteosarcoma.
- To elucidate the underlying molecular mechanisms of baicalin's anti-OS activity.
Main Methods:
- In vitro studies assessed cell death, proliferation, iron accumulation, and lipid peroxidation in OS cell lines (MG63, 143B).
- Biochemical assays measured glutathione (GSH/GSSG) and malondialdehyde (MDA) levels.
- Western blot analysis detected key proteins involved in ferroptosis regulation (Nrf2, GPX4, xCT).
- In vivo efficacy was evaluated using a xenograft mouse model.
Main Results:
- Baicalin significantly inhibited OS cell growth both in vitro and in vivo.
- Baicalin induced ferroptosis by increasing iron accumulation, ROS, and MDA, while decreasing the GSH/GSSG ratio.
- Ferrostatin-1 (Fer-1) reversed baicalin's effects, confirming ferroptosis involvement.
- Baicalin destabilized Nrf2 through ubiquitin degradation, suppressing downstream targets GPX4 and xCT, thereby promoting ferroptosis.
Conclusions:
- Baicalin demonstrates significant anti-osteosarcoma activity by inducing ferroptosis.
- The mechanism involves a novel Nrf2/xCT/GPX4-dependent regulatory axis.
- Baicalin represents a promising therapeutic candidate for osteosarcoma treatment.
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