文献类型：期刊文献

英文题名：LRP8 Promotes colorectal cancer progression by suppressing ferroptosis through the SLC3A2/GPX4 signalling axis

作者：Zhu, Chengzhang[1,3,4];Qian, Zhengpeng[2,3];Yang, Shijie[1,5];Wang, Yongfeng[1,6];Yang, Xiongfei[3,5];Du, Binbin[1,3,5];Cai, Hui[1,4,5,6]

第一作者：Zhu, Chengzhang

通信作者：Du, BB[1];Cai, H[1];Du, BB[2];Cai, H[3];Du, BB[4];Cai, H[4];Cai, H[5]

机构：[1]Lanzhou Univ, Sch Clin Med 1, 222 Tianshui South Rd, Lanzhou 730000, Gansu, Peoples R China;[2]Gansu Univ Chinese Med, Clin Med Coll 1, Lanzhou 730000, Gansu, Peoples R China;[3]Gansu Prov Hosp, Dept Anorectal Med, 204 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China;[4]Gansu Prov Hosp, NHC Key Lab Diag & Therapy Gastrointestinal Tumor, Lanzhou 730000, Gansu, Peoples R China;[5]Gansu Prov Hosp, Gen Surg Clin Med Ctr, Lanzhou 730000, Gansu, Peoples R China;[6]Gansu Prov Hosp, Key Lab Mol Diagnost & Precis Med Surg Oncol Gansu, Lanzhou 730000, Gansu, Peoples R China

第一机构：Lanzhou Univ, Sch Clin Med 1, 222 Tianshui South Rd, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Sch Clin Med 1, 222 Tianshui South Rd, Lanzhou 730000, Gansu, Peoples R China;[2]corresponding author), Gansu Prov Hosp, Dept Anorectal Med, 204 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China;[3]corresponding author), Gansu Prov Hosp, NHC Key Lab Diag & Therapy Gastrointestinal Tumor, Lanzhou 730000, Gansu, Peoples R China;[4]corresponding author), Gansu Prov Hosp, Gen Surg Clin Med Ctr, Lanzhou 730000, Gansu, Peoples R China;[5]corresponding author), Gansu Prov Hosp, Key Lab Mol Diagnost & Precis Med Surg Oncol Gansu, Lanzhou 730000, Gansu, Peoples R China.

年份：2026

卷号：31

期号：1

外文期刊名：EUROPEAN JOURNAL OF MEDICAL RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001714577700002)】；

基金：The work is supported by National Natural Science Foundation of China (No. 82360498), Gansu Joint Scientific Research Fund Major Project under Grant (No.23JRRA1537), The 2025 Central-Guided Local Science and Technology Development Found(No.25ZYJA003), Alpha isotope mass production technology and targeted radiopharmaceuticals research(No.GSTWS250108), and department of Health Commission of Gansu Province(No.GSWSKY2024-12).

语种：英文

外文关键词：LRP8; Colorectal cancer; Ferroptosis; GPX4; Iron metabolism

摘要：BackgroundColorectal cancer (CRC) persists as one of the most lethal malignancies worldwide, with therapeutic resistance representing a significant obstacle in clinical management. Ferroptosis, a form of programmed cell death triggered by iron accumulation and lipid peroxidation, has recently emerged as a promising target for cancer therapy. Although low-density lipoprotein receptor-related protein 8 (LRP8) has been implicated in oncogenic processes across cancer types, its involvement in CRC progression and ferroptosis regulation has not been fully elucidated.MethodsThis study utilized an integrative multi-omics approach, incorporating transcriptomic profiling across the colorectal carcinogenesis spectrum (normal mucosa, adenoma, carcinoma; n = 5 each) and proteomic analysis via 4D-DIA mass spectrometry. LRP8 expression patterns were examined in 40 paired CRC and adjacent normal tissues and a tissue microarray comprising 94 cases. Functional investigations were conducted in CRC cell lines following LRP8 knockdown or overexpression. Xenograft models were employed for in vivo validation. Mechanistic insights were gained through co-immunoprecipitation, redox assays, and transmission electron microscopy.ResultsTranscriptomic data revealed a stepwise increase in LRP8 expression during CRC development. Clinical analyses demonstrated that elevated LRP8 levels correlated significantly with advanced tumour stage, lymphatic metastasis, and poorer patient prognosis. Functional assays indicated that LRP8 enhances oncogenic behaviors by interacting with SLC3A2. Reintroducing SLC3A2 in LRP8-depleted cells restored glutathione peroxidase 4 (GPX4) expression and mitigated oxidative stress, thereby rescuing ferroptosis resistance. In vivo, silencing LRP8 inhibited tumour growth and induced ferroptosis-associated alterations, including disrupted iron homeostasis and increased lipid peroxidation.ConclusionLRP8 facilitates CRC progression by antagonizing ferroptosis via modulation of the SLC3A2/GPX4 signalling axis. These findings highlight LRP8 as a previously unrecognized regulator of ferroptotic vulnerability and a potential therapeutic target in CRC.