宫颈癌是全球癌症死亡的主要原因之一，铁死亡是宫颈癌进展的相关因素。玉米角家族AMPA受体辅助蛋白4（CNIH4）参与了多种人类癌症的进展，然而其在宫颈癌中的功能尚不清楚。本研究旨在通过体外增减功能研究，调查CNIH4在宫颈癌中的作用和机制。利用慢病毒载体感染SiHa和CaSki细胞以在体外操纵CNIH4的表达，评估细胞存活率、迁移、侵袭以及铁死亡。进一步进行转录组测序分析，来验证CNIH4调控宫颈癌进展的机制。CNIH4在人宫颈癌组织和细胞中上调表达，并与宫颈癌患者总生存率和无病生存率的下降密切相关。CNIH4静默抑制，而CNIH4过表达促进了人宫颈癌细胞的存活。机制上，CNIH4提升了溶质载体家族7成员11（SLC7A11）介导的半胱新酸进口，进而增加了细胞内谷胱甘肽合成和谷胱甘肽过氧化物酶4活性，从而抑制了人宫颈癌细胞的铁死亡。在体内，SLC7A11静默显著削弱了CNIH4介导的宫颈癌细胞铁死亡的抑制作用。我们的研究首次揭示了CNIH4通过上调SLC7A11抑制了人宫颈癌细胞的铁死亡，从而确定了CNIH4作为宫颈癌的治疗和预后靶点的吸引力。版权所有 © 2023 Elsevier B.V. 发表。

Cervical cancer is one of the most leading causes of cancer death worldwide, and ferroptosis is implicated in the progression of cervical cancer. Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) is involved in the progression of various human cancers; however, its function in cervical cancer remains unclear. The present study aims to investigate the role and mechanism of CNIH4 in cervical cancer using gain- and loss-of-function studies in vitro. SiHa and CaSki cells were infected with lentiviral vectors to manipulate the expression of CNIH4 in vitro, and cell viability, migration, invasion as well as ferroptosis were evaluated. Transcriptome sequencing analysis was performed to further validate the mechanism through which CNIH4 regulated the progression of cervical cancer. The expression of CNIH4 was upregulated in human cervical cancer tissues and cells, and strongly correlated with the decreases in overall survival and disease free survival rates of cervical cancer patients. CNIH4 silence inhibited, while CNIH4 overexpression facilitated the survival of human cervical cancer cells. Mechanistically, CNIH4 elevated solute carrier family 7 member 11 (SLC7A11)-mediated cystine import, and subsequently increased intracellular glutathione synthesis and glutathione peroxidase 4 activity, thereby inhibiting ferroptosis of human cervical cancer cells. SLC7A11 silence significantly abolished CNIH4-mediated inhibition of ferroptosis in cervical cancer cells in vitro. Our study for the first time reveals that CNIH4 inhibits ferroptosis of human cervical cancer cells through upregulating SLC7A11, defining CNIH4 as an attractive therapeutic and prognostic target for cervical cancer.Copyright © 2023. Published by Elsevier B.V.