RUSC1 (RUN and SH3 domain containing 1) is a multifunctional signaling adapter with roles in protein trafficking and cell signaling. The protein associates with the AP-4 complex and regulates vesicular trafficking at the trans-Golgi network and pre-synaptic membranes 1. RUSC1 acts as a signaling adapter promoting neuronal differentiation and NGF-dependent neurite outgrowth through MAPK-regulated pathways 2. It also regulates polyubiquitination of IKBKG, modulating NF-κB pathway signaling 3. Clinically, dysregulation of RUSC1-associated lncRNAs (RUSC1-AS1 and RUSC1-AS-N) represents a significant disease mechanism. These antisense transcripts are aberrantly upregulated in multiple cancers including breast cancer, osteosarcoma, and hepatocellular carcinoma, where they promote tumor progression 456789. RUSC1-AS1 promotes breast cancer and osteosarcoma through competing endogenous RNA mechanisms, sponging miR-340-5p and miR-326 to activate oncogenic PI3K/AKT and Wnt/β-catenin signaling 57. In hepatocellular carcinoma, RUSC1-AS1 activates NOTCH signaling via miR-7-5p sponging 6. Conversely, RUSC1-AS1 downregulation in type 2 diabetes inflammation suggests context-dependent roles 10. RUSC1-associated lncRNAs serve as prognostic biomarkers and potential therapeutic targets for cancer treatment.