While the tumor-suppressive functions of p53 are well established, the role of its homolog, TAp73, in cancer remains incompletely characterized and is a subject of active investigation. In this study, we observed downregulation of TAp73 protein expression in cervical cancer tissues, which significantly correlated with adverse clinical outcomes. Through co-expression network analysis, we identified functional associations between TAp73 and key pathways involved in lipid metabolism and redox homeostasis-both critical regulators of ferroptosis, an iron-dependent form of programmed cell death mediated by lipid peroxidation. Mechanistically, we demonstrate that TAp73 promotes ferroptosis by directly upregulating the transcription of β-transducin repeat-containing protein (β-TRCP), thereby facilitating the ubiquitin-dependent degradation of nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of cellular antioxidant defenses. This TAp73-mediated suppression of NRF2 activity renders cells more susceptible to ferroptotic death. Furthermore, TAp73 expression is transcriptionally induced during ferroptosis through the combined inactivation of enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, and activation of E2F transcription factor 1 (E2F1). Notably, pharmacological inhibition of EZH2 synergized with sulfasalazine (SAS) to enhance ferroptosis in vivo, an effect largely dependent on TAp73. Together, these findings delineate a novel ferroptosis regulatory axis-EZH2/TAp73/β-TRCP/NRF2-and highlight its potential as a therapeutic target for cervical cancer intervention.
Keywords: EZH2; NRF2; Oxidative homeostasis; TAp73.
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