HMBOX1 is a transcriptional repressor belonging to the homeobox family of transcription factors 1. Beyond its classical transcriptional functions, HMBOX1 plays a specialized role in telomere biology by directly binding 5'-TTAGGG-3' telomeric repeats and associating with the telomerase complex to positively regulate telomere elongation 2. In telomerase-negative cells, HMBOX1 promotes formation and maintenance of ALT-associated promyelocytic leukemia bodies and enhances telomere C-circle formation, suggesting involvement in alternative lengthening of telomeres and telomere recombination 3. HMBOX1 displays tissue-dependent functions with pathological relevance. In cardiac tissues, HMBOX1 inhibition protects against ischemia/reperfusion injury by promoting cardiomyocyte survival and glucose metabolism through glucokinase activation 4. In colorectal cancer, HMBOX1 downregulation correlates with 5-fluorouracil resistance; restoration of HMBOX1 expression enhances chemosensitivity by transcriptionally upregulating the E3 ubiquitin ligase HACE1, which promotes ATG5 degradation and inhibits autophagy 5. Additionally, HMBOX1 has been identified as an autoantigen in systemic sclerosis patients 6. These findings establish HMBOX1 as a multifunctional regulator with distinct roles in telomere maintenance, metabolic adaptation, chemoresistance, and autoimmune disease.