RNF180 is an E3 ubiquitin-protein ligase that functions as a tumor suppressor across multiple cancer types. As an E3 ubiquitin ligase, RNF180 catalyzes polyubiquitination and proteasomal degradation of multiple oncogenic substrates 12. RNF180 expression is frequently downregulated in cancer tissues through promoter methylation 3, with silencing observed in gastric cancer, osteosarcoma, non-small cell lung cancer, and colorectal cancer. Mechanistically, RNF180 suppresses tumorigenesis by ubiquitinating and degrading distinct substrate proteins depending on cancer context: CBX4 in osteosarcoma 1, WISP1 in colorectal cancer 4, NOTCH1/TRIM24/FOXC1 and ACC1/ACLY in colorectal cancer 2, IPO4 in ovarian cancer 5, C-myc in non-small cell lung cancer 6, and ZIC2 via UniProt annotation. RNF180 re-expression inhibits cell proliferation, promotes apoptosis, and suppresses migration and invasion in cancer cells. Clinically, RNF180 downregulation is associated with poor prognosis and treatment resistance 36. Methylated RNF180 DNA in plasma represents a promising biomarker for early detection in gastric and esophageal cancers 37. These findings establish RNF180 as a therapeutic target and prognostic indicator across multiple malignancies.