Unveiling CDKN2B-AS1: The functional long noncoding RNA driving age-related diseases

Senescence, a gradual decline in physiological functions, is closely linked to aging at both the cellular and organ levels. Emerging research has increasingly highlighted the role of long noncoding RNAs (lncRNAs)—a class of RNAs longer than 200 nucleotides that lack protein-coding potential—in regulating cellular senescence. Among them, cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), an antisense lncRNA located at the INK4 locus, has gained significant attention. Elevated levels of CDKN2B-AS1 have been observed in various tumor tissues, where its suppression has been shown to inhibit the proliferation, invasion, and migration of cancer cells. Recent studies have further implicated lncRNA CDKN2B-AS1 in age-related diseases (ARDs) including cardiovascular diseases (CVDs), diabetes, cancer, arthritis, and osteoporosis, by functioning as competing endogenous RNA (ceRNA), influencing inflammatory pathways, and regulating glucose metabolism. Deciphering the molecular mechanisms by which CDKN2B-AS1 mediates aging processes can enhance our understanding and provide new avenues for aging and ARD interventions. This review delved into the molecular mechanisms by which CDKN2B-AS1 influences ARD progression, offering insights into novel biomarkers and potential diagnostic tools while summarizing clinical treatment strategies in this context. A schematic figure of CDKN2B-AS1's role in driving ARDs. CDKN2B-AS1 contributes to aging and age-related diseases by influencing inflammation, vascular aging, metabolic regulation, neurodegeneration, and oncogenesis. Targeting CDKN2B-AS1 may offer therapeutic potential in mitigating aging-related pathologies. • Pan-disease synthesis of CDKN2B-AS1 functions Integrates >90 primary studies to map how the 9p21 lncRNA CDKN2B-AS1 drives cardiovascular, metabolic, neurodegenerative and malignant disorders through shared epigenetic and post-transcriptional circuits. • Unified mechanistic framework Dissects four convergent pathways—PRC2-mediated chromatin silencing, ceRNA sponging, AdipoR1/AMPK/SIRT1 metabolic control and NF-κB inflammatory signaling—linking CDKN2B-AS1 to cellular senescence and tissue degeneration. • EZH2 emerges as a druggable hub Highlights EZH2-centred CDKN2B-AS1/PRC2 complexes as a common effector in atherosclerosis, diabetic retinopathy and hepatocellular carcinoma, providing a tractable target for cross-disease intervention. • Genotype-to-phenotype bridge at 9p21.3 Clarifies how risk SNPs remodel CDKN2B-AS1 chromatin loops and CpG sites, connecting genome-wide association signals with β-cell failure, vascular aging and cancer susceptibility. • Therapeutic outlook Summarises emerging RNA-targeted modalities—ASOs, siRNAs and CRISPR epigenome editing—poised to translate CDKN2B-AS1 biology into first-in-class treatments for age-related diseases.