eng International Academy of Ecology and Environmental Sciences Network Biology 2220-8879 2026-12-1 16 4 525 551 4 article WenJun Zhang 1 2 School of Life Sciences, Sun Yat-sen University, Guangzhou, China Telomerase is a specialized ribonucleoprotein reverse transcriptase that maintains telomere length by adding repetitive DNA sequences to chromosome ends, thereby counteracting the progressive telomere shortening that occurs during DNA replication. The enzyme comprises two essential core components: the catalytic protein subunit telomerase reverse transcriptase (TERT) and the integral RNA component (TERC or hTR) that serves as the template for telomeric repeat synthesis. While telomerase is silenced in most normal human somatic tissues, it is reactivated in 85-90% of human cancers, making it an almost universal oncology target. Conversely, insufficient telomerase function underlies a spectrum of degenerative diseases collectively known as telomere biology disorders, including dyskeratosis congenita. This comprehensive review synthesizes current knowledge spanning the discovery, structure, biogenesis, and regulation of telomerase; its canonical and non-canonical functions in stem cell maintenance, tissue regeneration, immune function, and aging; its dual role as both a therapeutic target in cancer and a rejuvenation target in age-related diseases; and emerging frontiers including engineered telomerase RNA, CRISPR-based interventions, novel small-molecule activators such as TAC, artificial intelligence applications in drug discovery, and clinical progress with telomerase-based therapeutics. The review concludes with a critical assessment of remaining challenges and future research directions. http://www.iaees.org/publications/journals/nb/articles/2026-16(4)/Telomerase.pdf telomerase TERT TERC telomere cancer aging senescence telomerase inhibitor telomerase vaccine immunotherapy CRISPR AI drug discovery TAC engineered telomerase RNA clinical trials.