Linking metabolic reprogramming to JAK-STAT signaling in triple-negative breast cancer brain metastasis

Introduction: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype disproportionately affects younger patients and associated with high recurrence rates and rapid disease progression. TNBC cells that colonize the brain undergo extensive metabolic reprogramming to survive in this specialized microenvironment. Understanding the mechanisms by which TNBC cells adapt their metabolism and signaling networks to thrive in the brain niche is critical to uncovering novel vulnerabilities for therapeutic intervention. Materials and Methods: To address this knowledge gap, we conducted integrated metabolomic and transcriptomic analyses utilizing a TNBC brain metastasis (BM) xenograft mouse model, with validation in human patient-derived tissues. Metabolite profiling was performed using liquid chromatography-mass spectrometry equipped with an ACQUITY UPLC BEH C18 column. Matched samples from primary tumors, brain metastases, and serum were analyzed. Metabolite deconvolution employed AMDIS software, and compound identification was cross-referenced with NIST and HMDB spectral databases. Unique metabolites enriched in brain metastases and serum were identified and subjected to pathway enrichment analysis using MetaboAnalyst. To integrate metabolic findings with gene expression, pathway-associated genes were cross-referenced against transcriptomic datasets (GEO GSE76714), enabling network analysis of metabolite-gene interactions. Results: Our integrative analyses revealed that RNF125, an E3 ubiquitin ligase involved in immune regulation and oncogenesis, functions as a central regulatory node connecting metabolic pathways to the JAK-STAT signaling axis. RNF125 upregulation was inversely correlated with JAK3 activity, suggesting a role in modulating cytokine signaling to promote TNBC cell adaptation within the brain microenvironment. Conclusion: This study identifies RNF125 as a novel biomarker and potential therapeutic target in TNBC brain metastasis.