CDKN2C encodes a cyclin-dependent kinase inhibitor that functions as a cell cycle regulator and tumor suppressor. The protein interacts strongly with CDK6 and weakly with CDK4 to inhibit cell growth and proliferation through G1/S phase transition, with effects dependent on retinoblastoma protein function 1. CDKN2C operates as a critical negative regulator of cell proliferation and is involved in oligodendrocyte differentiation. Mechanistically, CDKN2C expression is transcriptionally regulated by multiple pathways. The transcription factor MAFF upregulates CDKN2C expression to promote ferroptosis and prevent G1/S progression in lung adenocarcinoma cells 1. Conversely, the polycomb repressive protein CBX8 directly binds CDKN2C promoters to establish repressive histone modifications (H2AK119ub) and silence CDKN2C expression, thereby promoting tumor cell proliferation and migration 2. CDKN2C alterations associate with multiple malignancies. Mutations occur in parathyroid carcinoma 3, and biallelic alterations appear in 17% of extramedullary multiple myeloma cases 4. CDKN2C functions as part of E2F signaling pathway alterations associated with prostate cancer recurrence 5. Notably, CDKN2C remains structurally unaltered in hepatoblastoma despite involvement in hepatocellular carcinoma pathogenesis 6. Clinically, reduced CDKN2C expression correlates with poor outcomes in lung adenocarcinoma and enhanced treatment resistance, suggesting therapeutic targeting of MAFF-mediated CDKN2C regulation may improve cisplatin and radiation efficacy 1.