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TFAP2C protects against ferroptosis in ovarian cancer through the KEAP1-NRF2 axis by recruiting HDAC1/2

Oncogene (2026)Cite this article

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Abstract

Ferroptosis, a distinct form of programmed cell death characterized by the iron-dependent aberrant buildup of lipid peroxides, has emerged as a promising approach in cancer therapy. The KEAP1-NRF2 axis serves as a critical regulator of ferroptosis, exerting its suppressive effects by preserving cellular redox homeostasis and orchestrating the transcriptional activation of downstream antioxidant genes. NRF2 hyperactivation is frequently observed across multiple cancer types and is associated with tumor progression and therapeutic resistance. Here, we identified the transcription factor TFAP2C as a novel regulator of the KEAP1-NRF2 signaling pathway in ovarian cancer (OC). TFAP2C knockdown inactivated KEAP1-NRF2 signaling, consequently reducing cell viability while inducing the accumulation of reactive oxygen species (ROS) and ferrous iron (Fe²⁺). Additionally, a decrease in the mitochondrial membrane potential (MMP) was observed upon TFAP2C knockdown. These alterations collectively triggered ferroptosis, thereby inhibiting the progression of OC to some extent. Moreover, NRF2 knockdown partially attenuated the pro-proliferative and ferroptosis-resistant phenotypes driven by TFAP2C overexpression in OC. ChIP and dual-luciferase reporter gene assays confirmed that TFAP2C transcriptionally repressed KEAP1 expression, thereby weakening the ubiquitination degradation of NRF2 by KEAP1. The upregulation of TFAP2C expression stabilized the NRF2 protein, activated the NRF2-dependent transcriptional program, and strengthened cellular antioxidant defenses, ultimately conferring resistance to ferroptosis. Mechanistically, TFAP2C bound to the promoter region of KEAP1 and recruited histone deacetylases 1/2 (HDAC1/2), resulting in the deacetylation of H3K27 and subsequent transcriptional repression of KEAP1. In summary, our mechanistic investigations revealed TFAP2C as a novel oncogenic driver in OC and a key regulator of ferroptosis via its epigenetic modulation of the KEAP1-NRF2 axis. These findings highlight TFAP2C as a potential therapeutic target for ferroptosis-inducing therapies in OC patients with high TFAP2C expression.

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Fig. 1: TFAP2C is frequently increased in ovarian cancer and is correlated with poor prognosis.
Fig. 2: TFAP2C facilitates the proliferation and xenograft growth of ovarian cancer cells.
Fig. 3: TFAP2C knockdown sensitizes ovarian cancer cells to ferroptosis.
Fig. 4: TFAP2C transcriptionally represses KEAP1 expression in ovarian cancer cells.
Fig. 5: TFAP2C interacts with HDAC1/HDAC2 and synergistically represses the KEAP1 expression through histone deacetylation.
Fig. 6: TFAP2C activates the KEAP1-NRF2 signaling pathway in ovarian cancer cells.
Fig. 7: TFAP2C regulates the proliferation and ferroptosis sensitivity of ovarian cancer cells through the KEAP1-NRF2 signaling pathway.
Fig. 8: Schematic diagram of TFAP2C-HDAC1/2-KEAP1-NRF2 axis regulating ferroptosis in ovarian cancer cells.

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Data availability

The supporting data for this study are provided in the supplementary materials. The raw ChIP-seq data are available upon request via email.

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Acknowledgements

The graphical abstract was created with the assistance of MedPeer (https://product.medpeer.cn/). We sincerely thank everyone who participated in and contributed to this study.

Funding

This research was supported by the National Natural Science Foundation of China (Grant No. 82403097), China Postdoctoral Science Foundation (Grant No. 2024M761831), and Shandong Postdoctoral Science Foundation (Grant No. SDCx-ZG-202400049).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China

    Guiyun Cheng, Wenwen Jiang, Zihan Li, Yana Ma & Xihan Liu

  2. Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, China

    Guiyun Cheng, Wenwen Jiang, Zihan Li, Yana Ma & Xihan Liu

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  1. Guiyun Cheng
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  2. Wenwen Jiang
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Contributions

GC conducted the experiments, analyzed the data, prepared the figures, and wrote the manuscript. WJ and ZL conducted animal experiments and contributed to manuscript writing. YM and XL designed the study, supervised the project, revised the manuscript, and provided funding.

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Correspondence to Yana Ma or Xihan Liu.

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Cheng, G., Jiang, W., Li, Z. et al. TFAP2C protects against ferroptosis in ovarian cancer through the KEAP1-NRF2 axis by recruiting HDAC1/2. Oncogene (2026). https://doi.org/10.1038/s41388-026-03692-1

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