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Baicalein triggers ferroptosis in colorectal cancer cells via blocking the JAK2/STAT3/GPX4 axis

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Colorectal cancer (CRC) is a prevalent form of gastrointestinal malignancy with challenges in chemotherapy resistance and side effects. Effective and low toxic drugs for CRC treatment are urgently needed. Ferroptosis is a novel mode of cell death, which has garnered attention for its therapeutic potential against cancer. Baicalein (5, 6, 7-trihydroxyflavone) is the primary flavone extracted from the dried roots of Scutellaria baicalensis that exhibits anticancer effects against several malignancies including CRC. In this study, we investigated whether baicalein induced ferroptosis in CRC cells. We showed that baicalein (1–64 μM) dose-dependently inhibited the viability of human CRC lines HCT116 and DLD1. Co-treatment with the ferroptosis inhibitor liproxstatin-1 (1 μM) significantly mitigated baicalein-induced CRC cell death, whereas autophagy inhibitor chloroquine (25 μM), necroptosis inhibitor necrostatin-1 (10 μM), or pan-caspase inhibitor Z-VAD-FMK (10 μM) did not rescue baicalein-induced CRC cell death. RNA-seq analysis confirmed that the inhibitory effect of baicalein on CRC cells is associated with ferroptosis induction. We revealed that baicalein (7.5–30 μM) dose-dependently decreased the expression levels of GPX4, key regulator of ferroptosis, in HCT116 and DLD1 cells by blocking janus kinase 2 (JAK2)/STAT3 signaling pathway via direct interaction with JAK2, ultimately leading to ferroptosis in CRC cells. In a CRC xenograft mouse model, administration of baicalein (10, 20 mg/kg, i.g., every two days for two weeks) dose-dependently inhibited the tumor growth with significant ferroptosis induced by inhibiting the JAK2/STAT3/GPX4 axis in tumor tissue. This study demonstrates that ferroptosis contributes to baicalein-induced anti-CRC activity through blockade of the JAK2/STAT3/GPX4 signaling pathway, which provides evidence for the therapeutic application of baicalein against CRC.

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Fig. 1: Ferroptosis induction is associated with anti-CRC effect of baicalein.
Fig. 2: Baicalein-mediated cytotoxicity is dependent on ferroptosis.
Fig. 3: Baicalein blocks JAK2/STAT3/GPX4 axis for ferroptosis induction.
Fig. 4: Baicalein promotes ferroptosis by targeting JAK2.
Fig. 5: Baicalein triggers ferroptosis in CRC xenograft model.
Fig. 6: Schematic illustration of baicalein-induced ferroptosis via JAK2/STAT3/GPX4 axis in CRC cells.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82173236, 81973341), Guangdong Basic and Applied Basic Research Foundation (2024A1515013108), the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Medical Joint Fund of Jinan University (YXJC2022002), Guangzhou High-level Key Clinical Specialty Construction Project (No.9), the Project of Key Medical Discipline in Guangzhou (2021–2023), Guangzhou Science and Technology Planning Project (202206080008), and 2023 Guangzhou digestive disease high-quality integrated treatment system construction project.

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  1. These authors contributed equally: Jian-qin Lai, Le-le Zhao, Chao Hong

Authors and Affiliations

  1. Department of General Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, China

    Jian-qin Lai & Jie Cao

  2. State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China

    Jian-qin Lai, Le-le Zhao, Chao Hong, Qiu-ming Zou, Jin-xuan Su, Si-jia Li, Xiao-feng Zhou, Zi-sheng Li & Qi Qi

  3. Department of General Surgery, Guangzhou First People’s Hospital, Guangzhou, 510180, China

    Jian-qin Lai & Jie Cao

  4. College of Pharmacy, Jinan University, Guangzhou, 510632, China

    Chao Hong

  5. The Affiliated Shunde Hospital of Jinan University, Foshan, 528305, China

    Bo Deng

  6. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China

    Qi Qi

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Contributions

JQL, QQ, and JC guided and designed the study; JQL performed all experiments. LLZ, CH, and QMZ provided the main technical support. SJL, JXS, XFZ, ZSL and BD contributed to the data collection and data analysis. JQL, QQ and BD wrote and revised the manuscript.

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Correspondence to Bo Deng, Jie Cao or Qi Qi.

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Lai, Jq., Zhao, Ll., Hong, C. et al. Baicalein triggers ferroptosis in colorectal cancer cells via blocking the JAK2/STAT3/GPX4 axis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01258-z

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