FJX1 drives FOLFOX resistance via PPARγ-mediated EMT and serves as a prognostic biomarker in colorectal cancer.

BACKGROUND: Four-jointed box 1 (FJX1) is aberrantly upregulated across multiple malignancies in tumor progression. However, its functional role in colorectal cancer (CRC), particularly in mediating chemoresistance and modulating the tumor immune microenvironment, remains poorly characterized. This study aimed to comprehensively elucidate the oncogenic functions of FJX1 and evaluate its potential as a prognostic biomarker and therapeutic target in FOLFOX-resistant CRC. METHODS: We analyzed pan-cancer FJX1 expression using TCGA and GEO datasets, constructing and validating a prognostic nomogram. Integrating multi-omics with functional validation in FOLFOX-resistant colorectal cancer (CRC), we discovered FJX1 regulates PPARγ pathways. FJX1-PPARγ physical interactions were confirmed via co-immunoprecipitation and proximity ligation assays. Furthermore, disrupting this axis using the PPARγ inverse agonist FX909 significantly impaired CRC cell proliferation, migration, and wound healing, highlighting FJX1 as a promising novel therapeutic target. RESULTS: FJX1 was significantly overexpressed in CRC tissues compared to adjacent normal mucosa and correlated with advanced TNM stage and reduced overall survival. FJX1-overexpressing cells exhibited enhanced proliferation and migration. FJX1 was particularly upregulated in FOLFOX non-responders CRC tissues. Mechanistically, FJX1 directly bound PPARγ in resistant cells, with GSEA confirming strong PPARγ pathway enrichment with CRC FOLFOX non-responders. PPARγ inhibitor, FX909 treatment disrupted FJX1-PPARγ interaction, downregulated FJX1 expression, and suppressed proliferation and migration. CONCLUSION: We identify FJX1 as a functional driver of FOLFOX resistance acting through direct PPARγ binding. The FJX1-PPARγ axis represents a novel therapeutic vulnerability; its pharmacological disruption restores chemosensitivity, positioning FJX1 as both a predictive biomarker and a tractable target for overcoming treatment resistance in CRC.