Bavachin Induces Ferroptosis Through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2021 Oct 28

PMID 34707773

Citations 61

Authors

Yi Luo

Xu Gao

Luetao Zou

Miao Lei

Junming Feng

Zhenming Hu

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is a new form of regulated cell death, which is mediated by intracellular iron. Although it is reported that bavachin has antitumour effects on several tumour cells and prompts the reactive oxygen species (ROS) generation, it is unclear whether ferroptosis can be induced by bavachin in osteosarcoma (OS) cells. In this study, we found that bavachin inhibits the viability of MG63 and HOS OS cell lines along with an increase in the ferrous iron level, ROS accumulation, malondialdehyde overexpression, and glutathione depletion. Moreover, iron chelators (deferoxamine), antioxidants (Vit E), and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) reverse bavachin-induced cell death. Bavachin also altered the mitochondrial morphology of OS cells, leading to smaller mitochondria, higher density of the mitochondrial membrane, and reduced mitochondrial cristae. Further investigation showed that bavachin upregulated the expression of transferrin receptor, divalent metal transporter-1, and P53, along with downregulating the expression of ferritin light chain, ferritin heavy chain, p-STAT3 (705), SLC7A11, and glutathione peroxidase-4 in OS cells. More importantly, STAT3 overexpression, SLC7A11 overexpression, and pretreatment with pifithrin- (P53 inhibitor) rescued OS cell ferroptosis induced by bavachin. The results show that bavachin induces ferroptosis via the STAT3/P53/SLC7A11 axis in OS cells.

Citing Articles

JAK/STAT signaling as a key regulator of ferroptosis: mechanisms and therapeutic potentials in cancer and diseases.

Dai Y, Cui C, Jiao D, Zhu X Cancer Cell Int. 2025; 25(1):83.

PMID: 40055704 PMC: 11889932. DOI: 10.1186/s12935-025-03681-6.

Osteosarcoma Cells and Undifferentiated Human Mesenchymal Stromal Cells Are More Susceptible to Ferroptosis than Differentiated Human Mesenchymal Stromal Cells.

Smirnova Y, Hanetseder D, Derigo L, Gasser A, Vaglio-Garro A, Sperger S Antioxidants (Basel). 2025; 14(2).

PMID: 40002376 PMC: 11852062. DOI: 10.3390/antiox14020189.

Research Progress on Natural Products That Regulate miRNAs in the Treatment of Osteosarcoma.

Wang L, Liu X, Lv H, Zhang H, Lin R, Xu S Biology (Basel). 2025; 14(1).

PMID: 39857292 PMC: 11759184. DOI: 10.3390/biology14010061.

Polydatin-Induced Shift of Redox Balance and Its Anti-Cancer Impact on Human Osteosarcoma Cells.

Cimmino A, Gioia M, Clementi M, Faraoni I, Marini S, Ciaccio C Curr Issues Mol Biol. 2025; 47(1).

PMID: 39852136 PMC: 11764470. DOI: 10.3390/cimb47010021.

Naringenin induces ferroptosis in osteosarcoma cells through the STAT3-MGST2 signaling pathway.

Li Y, Bai X J Bone Oncol. 2025; 50():100657.

PMID: 39835176 PMC: 11743371. DOI: 10.1016/j.jbo.2024.100657.

References

He H, Law B, Zhang N, Qiu C, Qu Y, Wu A . Bavachin Protects Human Aortic Smooth Muscle Cells Against -Glycerophosphate-Mediated Vascular Calcification and Apoptosis Activation of mTOR-Dependent Autophagy and Suppression of -Catenin Signaling. Front Pharmacol. 2020; 10:1427. PMC: 6930901. DOI: 10.3389/fphar.2019.01427. View

Lv H, Zhen C, Liu J, Shang P . PEITC triggers multiple forms of cell death by GSH-iron-ROS regulation in K7M2 murine osteosarcoma cells. Acta Pharmacol Sin. 2020; 41(8):1119-1132. PMC: 7468252. DOI: 10.1038/s41401-020-0376-8. View

Chen M, Jiang Y, Sun Y . KDM4A-mediated histone demethylation of SLC7A11 inhibits cell ferroptosis in osteosarcoma. Biochem Biophys Res Commun. 2021; 550:77-83. DOI: 10.1016/j.bbrc.2021.02.137. View

Zhao J, Zhao Y, Ma X, Zhang B, Feng H . Targeting ferroptosis in osteosarcoma. J Bone Oncol. 2021; 30:100380. PMC: 8319509. DOI: 10.1016/j.jbo.2021.100380. View

Su Y, Zhao B, Zhou L, Zhang Z, Shen Y, Lv H . Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett. 2020; 483:127-136. DOI: 10.1016/j.canlet.2020.02.015. View

Tarangelo A, Dixon S . The p53-p21 pathway inhibits ferroptosis during metabolic stress. Oncotarget. 2018; 9(37):24572-24573. PMC: 5973850. DOI: 10.18632/oncotarget.25362. View

Yang Y, Tang X, Hao F, Ma Z, Wang Y, Wang L . Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells. Biol Pharm Bull. 2017; 41(2):198-207. DOI: 10.1248/bpb.b17-00672. View

Yang W, Stockwell B . Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol. 2015; 26(3):165-176. PMC: 4764384. DOI: 10.1016/j.tcb.2015.10.014. View

Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X . Ferroptosis: process and function. Cell Death Differ. 2016; 23(3):369-79. PMC: 5072448. DOI: 10.1038/cdd.2015.158. View

10.

Lee Y, Lee J, Lim C . Anticancer activity of flavonoids accompanied by redox state modulation and the potential for a chemotherapeutic strategy. Food Sci Biotechnol. 2021; 30(3):321-340. PMC: 8017064. DOI: 10.1007/s10068-021-00899-8. View

11.

Wang Y, Zheng L, Ma B, Zhou Y, Zhang M, Zhang D . Clinical value of signal transducers and activators of transcription 3 (STAT3) gene expression in human osteosarcoma. Acta Histochem. 2010; 113(4):402-8. DOI: 10.1016/j.acthis.2010.03.002. View

12.

Tian Y, Lu J, Hao X, Li H, Zhang G, Liu X . FTH1 Inhibits Ferroptosis Through Ferritinophagy in the 6-OHDA Model of Parkinson's Disease. Neurotherapeutics. 2020; 17(4):1796-1812. PMC: 7851296. DOI: 10.1007/s13311-020-00929-z. View

13.

Jiang L, Kon N, Li T, Wang S, Su T, Hibshoosh H . Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015; 520(7545):57-62. PMC: 4455927. DOI: 10.1038/nature14344. View

14.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

15.

Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P . Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014; 15(2):135-47. DOI: 10.1038/nrm3737. View

16.

Zhu G, Murshed A, Li H, Ma J, Zhen N, Ding M . O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer. Cell Death Discov. 2021; 7(1):83. PMC: 8052337. DOI: 10.1038/s41420-021-00468-2. View

17.

Sadykova L, Ntekim A, Muyangwa-Semenova M, Rutland C, Jeyapalan J, Blatt N . Epidemiology and Risk Factors of Osteosarcoma. Cancer Invest. 2020; 38(5):259-269. DOI: 10.1080/07357907.2020.1768401. View

18.

Mou Y, Wang J, Wu J, He D, Zhang C, Duan C . Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019; 12(1):34. PMC: 6441206. DOI: 10.1186/s13045-019-0720-y. View

19.

Friedmann Angeli J, Shah R, Pratt D, Conrad M . Ferroptosis Inhibition: Mechanisms and Opportunities. Trends Pharmacol Sci. 2017; 38(5):489-498. DOI: 10.1016/j.tips.2017.02.005. View

20.

Brookes M, Chan C, Baljer B, Wimalagunaratna S, Crowley T, Ragbir M . Surgical Advances in Osteosarcoma. Cancers (Basel). 2021; 13(3). PMC: 7864509. DOI: 10.3390/cancers13030388. View