{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HMBOX1 is a multifunctional homeobox‐containing protein that acts primarily as a transcriptional repressor and integrator of diverse cellular processes. In the cardiovascular system, HMBOX1 is implicated in exercise‐induced cardiomyocyte growth and proliferation through its regulation by microRNAs such as miR‑222, suggesting that modulation of HMBOX1 expression can influence adaptive cardiac remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the tumor microenvironment, HMBOX1 functions as a negative regulator in immune cells; for example, in lymphatic endothelial cells, its targeting by exosomal miR‑1468‑5p leads to activation of the JAK2/STAT3 pathway and an immunosuppressive program that facilitates tumor escape, while in natural killer (NK) cells, HMBOX1 suppresses cytotoxic activity and interferon‑γ production through downregulation of the NKG2D/DAP10 signaling axis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, HMBOX1—also known as HOT1 or TAH1—directly binds double‐stranded telomeric DNA and associates with the active telomerase complex, thereby promoting telomere elongation and maintaining telomere homeostasis in both telomerase‐positive and alternative lengthening (ALT) tumor cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Within vascular endothelial cells, HMBOX1 supports cell survival by promoting autophagy and inhibiting apoptosis. This protective role is mediated, at least in part, by its regulation of intracellular free zinc levels via an interaction with metallothionein 2A (MT2A), as well as by its capacity to counteract pro‐inflammatory and oxidative stress signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer, HMBOX1 appears to exert context‐dependent effects. In liver, ovarian, and glioma models, decreased expression of HMBOX1 is associated with enhanced proliferation, reduced apoptosis, and chemoresistance—pointing to a tumor‐suppressive role."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": " In contrast, HMBOX1 is upregulated in gastric cancer where it correlates with increased cell proliferation, migration, and an aggressive clinical phenotype, suggesting that its functions can be co‑opted to support tumor progression in certain settings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Moreover, in ovarian cancer, a specific tRNA‑derived fragment (tRF‑03357) promotes cell proliferation, migration and invasion by targeting and downregulating HMBOX1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in cell survival and tumorigenesis, HMBOX1 is crucial in developmental processes. It functions as a key regulator in the differentiation of embryonic stem cells into vascular endothelial cells by acting upstream of fibroblast growth factor 2 (FGF‑2) signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Alternative splicing of HMBOX1 (producing the HMBOX1b variant) further highlights its regulatory versatility, as the splice variant lacks a full homeodomain and exhibits attenuated transcriptional repressive activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In addition, HMBOX1 has been identified as a fusion partner in ALK‐rearranged sarcomas, suggesting its involvement in oncogenic events"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", and epigenetic modifications within the HMBOX1 locus have been linked to birthweight outcomes, underscoring its broader physiological relevance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies demonstrate that HMBOX1 is a versatile regulator of transcription, telomere maintenance, cell survival, immune modulation, and differentiation. Its context‐dependent activities have significant implications in cardiovascular physiology, immunology, and oncology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiaojun Liu, Junjie Xiao, Han Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2015.02.014"}], "href": "https://doi.org/10.1016/j.cmet.2015.02.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25863248"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25863248"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Chenfei Zhou, Wenfei Wei, Jing Ma, et al. 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