RBMX promotes colorectal liver metastasis by stabilizing MTHFD2 mRNA to regulate redox homeostasis.

BACKGROUND: Liver metastasis is the primary cause of mortality in colorectal cancer (CRC), yet the molecular mechanisms driving colorectal liver metastasis (CRLM) remain poorly understood. This study investigates the role of RNA-binding motif protein X (RBMX) in CRLM progression and its underlying mechanisms.

METHODS: RBMX expression and clinical significance were analyzed in public databases (GEO, TCGA) and in-house cohorts. Metastatic function was assessed using in vitro and in vivo models. Mechanistically, RNA sequencing, RNA immunoprecipitation (RIP), and RNA pull-down assays were employed to identify downstream targets. Metabolic profiling, reactive oxygen species (ROS) quantification, and signaling pathway analyses were used to evaluate redox homeostasis.

RESULTS: RBMX was upregulated in CRLM tissues and correlated with poor prognosis. It significantly promoted CRC cells migration, invasion, and liver metastasis. Mechanistically, RBMX directly bound to and stabilized MTHFD2 mRNA, increasing its protein abundance. This upregulation rewired one-carbon metabolism to boost NADPH production, effectively buffering intracellular ROS. Consequently, RBMX suppressed ROS-dependent p38/JNK stress signaling, sustaining metastatic cell survival.

CONCLUSIONS: Our study reveals that RBMX drives CRLM by stabilizing MTHFD2 mRNA to maintain redox homeostasis. This "RBMX-MTHFD2-Redox" axis links RNA stability to metabolic plasticity, representing a novel mechanistic vulnerability in CRLM and promising candidate for preclinical therapeutic development and biomarker investigation.