{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Chemokine‐like factor (CKLF)‐like MARVEL transmembrane domain–containing protein 2 (CMTM2) is a multifunctional transmembrane protein that bridges classical chemokines with the TM4SF (transmembrane 4 superfamily) and plays diverse roles in human physiology and pathology. Altered expression and epigenetic modifications of CMTM2 have been documented in several malignancies. For example, in glioblastoma, colorectal, hepatocellular, lung, and diffuse‐type gastric cancers, changes in CMTM2 expression—often via promoter hypermethylation—correlate with tumor progression, vascular invasion, and metastasis, suggesting that CMTM2 may function as a tumor suppressor in these contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": " In addition, epigenetic profiling in Sézary syndrome has revealed that CMTM2 promoter hypermethylation can serve as a distinguishing marker for this cutaneous T‐cell malignancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in cancer, CMTM2 is critically involved in male reproductive function. It is highly expressed in the testis and localizes to key regions of the sperm membrane where sperm–egg fusion occurs. Functional studies using rodent models have demonstrated that loss of CMTM2 leads to impaired spermiogenesis, reduced testicular size, and diminished sperm count, whereas overexpression can enhance steroidogenesis and elevate serum testosterone levels. Moreover, genetic variations in the CMTM2 promoter have been linked to alterations in litter size in goats, underscoring its importance in reproductive performance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, CMTM2 exerts immunomodulatory and antiviral effects. Intracellular CMTM2 has been shown to act as a negative regulator of HIV‐1 transcription by suppressing AP‐1 and CREB signaling pathways, and its degradation via the ubiquitin–proteasome system is implicated in HBV‐related disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Altered CMTM2 expression in immune cells may also contribute to the pathogenesis of autoimmune conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CMTM2 is a pleiotropic protein involved in the regulation of tumor progression, spermatogenesis, steroidogenesis, and immune responses. Its differential expression and epigenetic alteration in diverse diseases render it a promising biomarker and potential therapeutic target.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sabit Delic, Andreas Thuy, Markus Schulze, et al. 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