{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCardiac‐specific microRNA‐208a, encoded within myosin heavy chain genes, is a pivotal regulator of myocardial gene expression in both health and disease. Multiple studies have shown that miR‐208a is essential for proper cardiac development and function, contributing to myosin heavy chain isoform switching, pathological hypertrophy, fibrosis, and arrhythmia, while its circulating levels mark myocardial injury and infarction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": " Developmental studies further indicate that miR‐208a expression declines with gestational age, reflecting dynamic changes in cardiomyocyte proliferation and apoptosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and its circulating levels have been correlated with the severity of coronary atherosclerosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its intrinsic role in cardiac biology, miR‐208a has emerged as a promising diagnostic and prognostic biomarker in cardiovascular disease. Elevated plasma miR‐208a levels have been used to accurately diagnose acute myocardial infarction and predict adverse outcomes such as no-reflow phenomena and major adverse cardiac events following primary percutaneous coronary intervention."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Similarly, in pediatric patients undergoing corrective heart surgery, lower preoperative levels of miR‐208a have been associated with a higher risk of postoperative complications"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", while its overall prognostic potential in acute myocardial infarction has been further underlined."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAccumulating evidence also implicates miR‐208a as a multifaceted modulator in oncogenesis. In the tumor microenvironment, exosome‐mediated delivery of miR‐208a enhances osteosarcoma cell viability, migration, and clonogenicity by downregulating PDCD4 and activating the ERK1/2 pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In pancreatic cancer cells, miR‐208 overexpression induces epithelial–mesenchymal transition by altering the expression of hallmark markers via the AKT/GSK‑3β/snail signaling axis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In gastric cancer, high miR‐208a levels are associated with lymph node metastasis and advanced TNM stage, acting through the suppression of SFRP1 and negative regulation of MEG3."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Moreover, in hepatocellular carcinoma and non‐small cell lung cancer, upregulated miR‐208 variants contribute to tumor cell proliferation and invasion by targeting ARID2 and SRCIN1, respectively"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", and in ovarian cancer, the miR‑208a/DAAM1 axis has been shown to suppress tumor cell migration and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies highlight the broader regulatory network of miR‐208a across pathological conditions. In the emerging field of reverse cardio‐oncology, secreted miR‐208a not only exacerbates cardiac injury, remodeling, and arrhythmia but may also enhance tumor proliferation and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Mechanistically, miR‐208a modulates intercellular signaling; for example, it mediates the regulation of Bcl‑2 expression in cardiac fibroblasts in interplay with miR‑499 under mechanical stretch conditions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", and it governs mitochondrial biogenesis and function in cardiomyocytes subjected to metabolic stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Furthermore, in renal ischemia/reperfusion injury, miR‐208a‑3p—whose expression is controlled by circular RNAs—ameliorates tubular epithelial apoptosis, inflammation, and ferroptosis, while its altered serum levels in osteoporosis patients point to its potential as a biomarker in extra‐cardiac tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emanuela Bostjancic, Nina Zidar, Dusan Stajer, et al. 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