ARL4C is a small GTP-binding protein that regulates intracellular transport and cellular morphogenesis through its role in vesicular trafficking and cytoskeletal dynamics. The protein cycles between inactive GDP-bound and active GTP-bound states, recruiting cytohesin proteins to the plasma membrane and activating downstream signaling cascades involving ARF6, PI3K-Akt, and MAPK pathways. During normal development, ARL4C is minimally expressed in adult tissues but is essential for tubulogenesis and hippocampal neuron migration and dendritogenesis 1. ARL4C is substantially upregulated across multiple cancer types—including colorectal, gastric, lung, hepatocellular carcinoma, and clear cell renal cell carcinoma—where it drives tumor progression and metastasis. In these contexts, ARL4C promotes epithelial-to-mesenchymal transition, cell proliferation, invasion, and migration, largely through Wnt/β-catenin and growth factor-Ras signaling 234. In colorectal cancer, ARL4C overexpression mediates oxaliplatin resistance by activating RAP1/PI3K-Akt-mTOR signaling and stabilizing itself through USP38-mediated deubiquitination 5. Beyond cancer, ARL4C drives rheumatoid arthritis progression by promoting fibroblast-like synoviocyte proliferation and macrophage polarization 6. Therapeutic targeting strategies include ARL4C inhibition with β-Lapachone, which promotes protein degradation and restores chemotherapy sensitivity in oxaliplatin-resistant colorectal cancer, and antisense oligonucleotides, which reduce tumor growth in hepatocellular carcinoma and colorectal cancer liver metastases 57. AKT pathway inhibitors including hydroxycamptothecin decrease ARL4C expression in lung adenocarcinoma by promoting ubiquitin-proteasomal degradation 8.