The small Rho GTPase Rif promotes cancer progression through ERK2-mediated epithelial-mesenchymal transition

<p indent="0mm">Cancer remains one of the most formidable global health challenges, demanding a comprehensive exploration of its molecular underpinnings to advance therapeutic innovation. Tumorigenesis is driven by interrelated pathological processes such as metastatic dissemination, therapy resistance, and immune evasion, which are intricately linked to epithelial-mesenchymal transition (EMT). Rif, a member of the Rho GTPase family, has been implicated as an important modulator of oncogenic transformation. Through systematic investigation across various solid tumors, we identify Rif overexpression as a biomarker of histopathological aggressiveness and poor survival outcomes in breast, ovarian, and stomach tumors. Rif facilitates oncogenic progression by suppressing apoptosis and promoting cell proliferation, metastasis, and EMT induction. Integrated multiomics and functional profiling have revealed ERK2 as a key downstream effector of Rif’s protumorigenic effects. While engaging with tumor-specific signaling contexts (<italic>e</italic>.<italic>g</italic>., AHR, TGF-β/SMAD3), the Rif-ERK2 axis may represent a conserved and actionable target across various solid tumors. Targeted disruption of pathological signaling pathways may provide a novel approach to impede cancer aggressiveness and improve clinical outcomes in oncology.