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

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.