CDKN2AIP (CDKN2A interacting protein), also known as CARF, is a multifunctional regulator of cellular stress responses with primary roles in DNA damage recognition and metabolic homeostasis. Mechanistically, CDKN2AIP recognizes alkylated DNA lesions, specifically O6-methylguanine base pairs, functioning as a reader protein for mutagenic DNA damage 1. The protein also interacts with the exonuclease XRN2 through a conserved XRN2 binding domain to regulate ribosomal RNA processing 2. In metabolic contexts, CDKN2AIP responds to fatty acid excess by regulating endoplasmic reticulum and oxidative stress pathways; its downregulation during hepatic lipid overload contributes to fatty liver development, while overexpression ameliorates high-fat-diet-induced steatosis and insulin resistance 3. Clinically, CDKN2AIP functions as a tumor suppressor across multiple cancer types. In testicular seminoma, CDKN2AIP upregulation induces cell senescence and apoptosis through CARM1 and eIF4β interactions 4. In hepatocellular carcinoma, the transcription factor NR4A3 directly upregulates CDKN2AIP expression, suppressing proliferation and inducing G0/G1 cell cycle arrest 5. Additionally, circFOXP1 promotes angiogenesis in osteosarcoma by upregulating CDKN2AIP through miR-127-5p sequestration 6. CDKN2AIP mutations appear as candidate drivers in canine hemangiosarcoma (11% frequency) 7. Importantly, CDKN2AIP is regulated as a direct target gene by the transcription factors HNF4A and HNF1A in a tissue-dependent manner 8, positioning it within broader metabolic and developmental gene networks.