{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‐4458 has emerged as a multifaceted regulatory microRNA that plays a tumor‐suppressive role by modulating metabolic reprogramming and proliferation. In colon cancer cells, miR‐4458 directly targets hexokinase 2 (HK2) to inhibit glycolysis and lactate production, thereby suppressing cell growth. In addition, microarray studies in hepatocellular carcinoma have shown its downregulation, and in lung epithelial cells infected with Burkholderia pseudomallei, upregulation of miR‐4458 (along with related miRNAs) targets ATG10 to inhibit autophagy and facilitate bacterial survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn breast cancer, especially triple‐negative subtypes, miR‐4458 is frequently downregulated and acts as a key inhibitor of tumor progression. Its tumor‐suppressive effects are mediated in part through the direct targeting of oncogenic transcripts such as CPSF4 and suppressor of cytokine signaling 1 (SOCS1), resulting in reduced proliferation, migration, and enhanced apoptosis. Moreover, long non‐coding RNAs such as HEIH have been shown to sequester miR‐4458, thereby relieving repression of downstream oncogenic targets and contributing to tumor advancement."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these contexts, miR‐4458 exerts its anti‐tumor activity in a variety of other malignancies. In osteosarcoma, aberrantly expressed long non‐coding RNAs such as KCNQ1OT1 and CDKN2B‐AS1 act as molecular sponges for miR‐4458, leading to upregulation of targets including CCND2 and MAP3K3 that drive cell proliferation and migration. In hepatocellular carcinoma, miR‐4458 targets transforming growth factor beta receptor 1 (TGFBR1) to block TGF‐β signaling and epithelial‐mesenchymal transition. Likewise, in acute myeloid leukemia and gastric cancer, lncRNAs (LINC00665 and LINC00963, respectively) reduce miR‐4458 levels, resulting in the derepression of targets such as DOCK1 and ATG16L1 that modulate cell adhesion, autophagy, and chemoresistance. In melanoma and non‐small cell lung cancer, miR‐4458 limits tumor aggressiveness by targeting PBX3 and STAT3, the latter leading to decreased PD‐L1 expression and enhanced anti‐tumor immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dan Tang, Baomu Sun, Hongyu Yu, et al. 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