{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed that miR‑424 plays a pivotal role in vascular homeostasis and hypoxic adaptation. In endothelial cells, hypoxia‐induced miR‑424 targets key components of the ubiquitin–proteasomal machinery—specifically by suppressing cullin 2—to stabilize HIF‑1α and thereby promote angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, in pulmonary arterial endothelial cells the miR‑424/503 cluster modulates fibroblast growth factor (FGF) signaling by directly targeting FGF2 and FGFR1, an action that is essential for maintaining vascular integrity and preventing pulmonary hypertension; similar regulatory contributions have also been observed in mediating cross‐talk between the vascular endothelium and cardiomyocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of cancer biology, miR‑424 has emerged as a central regulator with context‑dependent tumor‐suppressive and oncogenic functions. In several malignancies – including cervical, endometrial, hepatocellular, and basal‑like breast cancers – miR‑424 is frequently downregulated, and its loss contributes to unchecked proliferation, chemoresistance, and impaired apoptosis by failing to restrain key cell cycle and survival regulators such as checkpoint kinase 1, Akt–E2F signaling components, and E2F7."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": " Furthermore, miR‑424 directly targets transcripts such as those encoding Akt3, E2F3, and the transcription factor PBX3, whose deregulation contributes to the maintenance of tumor‑initiating cells (TICs) in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In addition, long noncoding RNAs—including OIP5‑AS1 and PVT1—exert oncogenic effects in cervical cancer by sponging miR‑424, thereby relieving suppression of their downstream targets, while in ovarian and triple‑negative breast cancers, restoration of miR‑424 levels reverses chemoresistance and modulates immune checkpoints such as PD‑L1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "16"}]}, {"type": "t", "text": " In prostate cancer, however, miR‑424 upregulation impairs the function of an E3 ubiquitin ligase (COP1), leading to enhanced stabilization of oncogenic STAT3 and promoting malignant traits; similarly, in basal‑like breast cancer, miR‑424 suppresses cell proliferation, migration, and invasion via targeting DCLK1, and in osteosarcoma it acts by repressing cyclin A2 expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": " Notably, in non‑small‑cell lung cancer, pharmacological modulation of miR‑424‑3p levels has been shown to affect the PTEN/PI3K/Akt signaling cascade and alter cisplatin sensitivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in vascular regulation and tumor biology, miR‑424 is also intimately involved in cellular differentiation and tissue homeostasis. In myoblasts, induction of the miR‑424/503 cluster promotes G1 cell cycle arrest and facilitates muscle differentiation through downregulation of Cdc25A."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In the placenta, elevated miR‑424 levels are correlated with fetal growth restriction, concomitant with reduced expression of MEK1 and FGFR1, suggesting that miR‑424 contributes to placental developmental processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Additionally, miR‑424 has been implicated in the regulation of protein synthesis in skeletal muscle, being elevated in conditions such as chronic obstructive pulmonary disease and even proposed as a potential biomarker in neuromuscular disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Finally, delivery of miR‑424‑5p via extracellular vesicles has been demonstrated to modulate antitumor immune responses by impacting PD‑L1 expression, highlighting its therapeutic potential in immunomodulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Goutam Ghosh, Indira V Subramanian, Neeta Adhikari, et al. 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