TAp73 Modulates Proliferation and Ferroptosis in Mammary Epithelial Cells

Wenqiang Sun Hanjun Ren Le Chen Bingfei Zhang Liping Mei Jiaqi Wen Yilu Zhang Jiaqi Li Yongping Yan Songjia Lai ^*

• Sichuan Agricultural University, Ya'an, Sichuan, China

TAp73, a splice variant of the p73 gene, plays a critical role in the development of epithelial tissues.Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and ROS accumulation, has recently garnered increasing attention; however, its involvement in epithelial cells remains inadequately explored. In this study, we investigate the regulatory role of TAp73 in epithelial cells and its potential involvement in ferroptosis. Ectopic expression of TAp73 significantly upregulated p21 expression, resulting in decreased colony formation and DNA synthesis, thereby inhibiting cell proliferation. In contrast, TAp73 knockdown reduced p21 expression, enhanced colony formation and promoted cell proliferation. Additionally, treatment with the ferroptosis inducer RSL3 led to a dosedependent increase in cell death and ROS accumulation, confirming that epithelial cells can undergo ferroptosis. RSL3 treatment also elevated the expression of ferroptosis-related genes PTGS2 and TRFC.We further examined the regulation of ferroptosis by TAp73 and found that TAp73 ectopic expression significantly enhanced the expression of PTGS2 and TRFC, indicating enhanced susceptibility to ferroptosis. Conversely, TAp73 knockdown reduced the expression of these genes, thereby mitigating RSL3-induced ferroptosis and associated oxidative stress and lipid peroxidation. Collectively, these TAp73 Regulates Epithelial Cell Death 2 findings highlight TAp73 as a key regulatory factor in both cell proliferation and ferroptosis, offering new insights into potential therapeutic targets for controlling cell death in epithelial tissues.