ACYP2 (acylphosphatase 2) is an enzyme with acylphosphatase activity that demonstrates significant involvement in cancer biology and therapeutic resistance. The protein exhibits dual subcellular localization in both cytoplasm and nucleus, mediating distinct regulatory mechanisms 1. In hepatocellular carcinoma (HCC), cytoplasmic ACYP2 negatively regulates KCNN4, inhibiting K+ outflow and inactivating the ERK pathway, while nuclear ACYP2 inhibits TERT activity, reducing telomere length and reversing cell immortalization 1. ACYP2 functions as a tumor suppressor in HCC, where low expression correlates with poor prognosis and increased tumor aggressiveness 1. Conversely, in glioblastoma, ACYP2 promotes temozolomide resistance by upregulating c-Myc transcription factor, which enhances PARP1-mediated DNA damage repair 2. Multiple genetic polymorphisms in ACYP2 are associated with cancer susceptibility, with several variants increasing risk across various malignancies 34. The gene also influences telomerase activity and telomere length regulation 5. Additionally, ACYP2 polymorphisms are linked to cisplatin-induced ototoxicity in pediatric cancer patients 6. These findings establish ACYP2 as a context-dependent regulator with potential therapeutic implications in cancer treatment.