Wang Hongyou, Zhou Jianbo, Zhang Jianfeng, Yao Wenlei, Li Haiyang, Xu Kangjie, Cheng Hui
Department of Obstetrics and Gynecology, Binhai County People's Hospital, Yancheng, 224500, Jiangsu, China.
Department of Chinese and Western Medicine Integrative Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
J Mol Histol. 2025 Sep 19;56(5):320. doi: 10.1007/s10735-025-10603-3.
Transferrin receptor (TFRC) is essential for iron uptake and may regulate ferroptosis, a form of iron-dependent cell death implicated in cervical cancer (CC). Bioinformatic analyses (GEPIA, UALCAN, SRAMP, starBase) were combined with in vitro and in vivo experiments. CC cell lines were transfected with shRNAs or overexpression plasmids targeting TFRC and LOXL1-AS1. Proliferation was assessed by colony formation, EdU staining, and Ki-67 immunostaining. Ferroptosis was evaluated by measuring malondialdehyde (MDA), lipid ROS, Fe⁺, and ferroptosis-related proteins. RNA pull-down, RIP, and MeRIP assays were used to explore m6A-dependent regulation, and actinomycin D assays assessed mRNA stability. TFRC and LOXL1-AS1 were upregulated in CC and associated with poor prognosis. TFRC promoted CC cell proliferation and inhibited ferroptosis. LOXL1-AS1 positively regulated TFRC by stabilizing its mRNA via an m6A-IGF2BP2-dependent mechanism. Rescue experiments confirmed that TFRC overexpression reversed the effects of LOXL1-AS1 knockdown. In vivo, LOXL1-AS1 depletion suppressed tumor growth and enhanced ferroptosis. LOXL1-AS1 promoted CC progression by stabilizing TFRC mRNA through m6A-IGF2BP2 interaction, suppressing ferroptosis. Targeting the LOXL1-AS1/IGF2BP2/TFRC axis may offer a potential therapeutic strategy for CC.
转铁蛋白受体（TFRC）对铁摄取至关重要，可能调控铁死亡，这是一种与宫颈癌（CC）相关的铁依赖性细胞死亡形式。将生物信息学分析（GEPIA、UALCAN、SRAMP、starBase）与体外和体内实验相结合。用靶向TFRC和LOXL1-AS1的短发夹RNA（shRNAs）或过表达质粒转染CC细胞系。通过集落形成、EdU染色和Ki-67免疫染色评估细胞增殖。通过测量丙二醛（MDA）、脂质活性氧（ROS）、Fe⁺和铁死亡相关蛋白来评估铁死亡。采用RNA下拉、RNA免疫沉淀（RIP）和甲基化RNA免疫沉淀（MeRIP）实验来探索m6A依赖性调控，并用放线菌素D实验评估mRNA稳定性。TFRC和LOXL1-AS1在CC中上调，并与不良预后相关。TFRC促进CC细胞增殖并抑制铁死亡。LOXL1-AS1通过一种依赖m6A-IGF2BP2的机制稳定TFRC的mRNA，从而正向调控TFRC。挽救实验证实TFRC过表达可逆转LOXL1-AS1敲低的作用。在体内，LOXL1-AS1缺失抑制肿瘤生长并增强铁死亡。LOXL1-AS1通过m6A-IGF2BP2相互作用稳定TFRC mRNA，抑制铁死亡，从而促进CC进展。靶向LOXL1-AS1/IGF2BP2/TFRC轴可能为CC提供一种潜在的治疗策略。
