LRP2-mediated regulation of ferroptosis through the Wnt/β-catenin-GPX4 axis in colorectal cancer liver metastasis and chemoresistance.

Shasha Zhao, Limei Sun, Jing Xia, Sen Yan, Baohua Zhang, Buyou Lu, Nan Huang, Fenyong Sun, Fuming Shen

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Article in Cell death discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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9 authors.

Shasha Zhao *Department of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Limei Sun *Department of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Jing XiaDepartment of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Sen YanDepartment of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Baohua ZhangDepartment of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Buyou LuDepartment of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.

Nan HuangDepartment of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. 2205565@tongji.edu.cn.ORCID http://orcid.org/0000-0001-7198-2636

Fenyong SunDepartment of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. sun_fenyong@163.com.

Fuming ShenDepartment of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. fumingshen@tongji.edu.cn.

Funding

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6 · The paper itself

Abstract

Colorectal cancer liver metastasis (CRLM) is a major contributor to cancer mortality, and therapeutic efficacy is often limited by chemoresistance. Dysregulated lipid metabolism has been implicated in tumor progression, yet the function of low-density lipoprotein receptor-related protein 2 (LRP2) in CRLM and oxaliplatin (Oxa) resistance has not been defined. We integrated bioinformatics analyses of TCGA and GSE131418 datasets with in vitro and in vivo experiments to investigate the role of LRP2 in CRLM. Untargeted metabolomics, ferroptosis assays, and mechanistic studies were employed to characterize the Wnt/β-catenin-GPX4 axis. LRP2 was markedly upregulated in CRLM and associated with poor survival. Silencing LRP2 inhibited colorectal cancer (CRC) cell proliferation, migration, and liver metastasis, while enhancing sensitivity to Oxa. LRP2 depletion induced ferroptosis, which was rescued by ferroptosis inhibition. Mechanistically, LRP2 activated Wnt/β-catenin signaling, driving GPX4 expression through TCF1-mediated transcription. LRP2 promotes CRLM and Oxa resistance by repressing ferroptosis via the Wnt/β-catenin-TCF1-GPX4 pathway. Targeting this signaling cascade may provide a therapeutic strategy for metastatic CRC.

Identifiers

PMID42215454

DOI10.1038/s41420-026-03161-4

PMCPMC13424328

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