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

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.