{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed that miR‐451a is generated by an unusual, non‐canonical biogenesis pathway that distinguishes it from the vast majority of animal microRNAs. Instead of the typical sequential Drosha–Dicer processing, its maturation depends on Drosha cleavage of a short hairpin precursor followed by direct Ago2‐mediated cleavage and subsequent 3′ trimming by PARN. This alternative processing route not only highlights its evolutionary conservation but also suggests that miR‐451a may serve as a model for Dicer‐independent gene regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn diverse cancer types miR‐451a appears to play a multifaceted tumor‐suppressive role. In breast cancer, for example, altered miR‐451a expression is involved in regulating drug resistance through modulation of multidrug transporter proteins such as P‐glycoprotein and the MDR1 gene product, with restoration of miR‐451a enhancing cellular sensitivity to chemotherapeutics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In brain tumors such as glioblastoma, its levels are dynamically tuned in response to glucose availability to govern the balance between proliferation and migration via the LKB1/AMPK pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In non‐small cell lung cancer, colorectal, hepatocellular, and papillary thyroid carcinomas, miR‐451a targets key oncogenic effectors—including RAB14, components of the PI3K/Akt/mTOR cascade (via regulators such as CAB39 and TSC1), BAP31, YWHAZ and c‐Myc—to suppress proliferation, invasion, epithelial–mesenchymal transition and to promote apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "16"}]}, {"type": "t", "text": " Moreover, modulation of miR‐451a expression has been linked to altered cellular responses in additional malignancies: in docetaxel‐resistant lung adenocarcinoma its re‐expression reverses an EMT‐like phenotype"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", while in T cell acute lymphoblastic leukemia and chronic myeloid leukemia deregulated miR‐451a contributes to oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Importantly, several reports also highlight its potential diagnostic and therapeutic value: altered miR‐451a levels in cancer stem cell subpopulations, circulating exosomes and tumor tissues (including colorectal cancer, multiple myeloma, pancreatic neoplasms, and hepatocellular carcinoma) correlate with tumor aggressiveness, chemoresistance and prognosis, thus positioning miR‐451a as a promising biomarker and target for tailored anticancer strategies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in oncogenesis, miR‐451a is emerging as an important regulator in non‐malignant as well as systemic pathologies. In cardiovascular diseases, for instance, reduced miR‐451a expression has been implicated in the regulation of cardiomyocyte growth, autophagy, and hypertrophy by directly targeting components such as TSC1, thereby modulating mTOR activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": " In parallel, aberrant miR‐451a levels have been observed in autoimmune and neuropsychiatric disorders; its dysregulation in conditions such as autoimmune arthritis, major depression, and even autism spectrum disorders suggests that miR‐451a may influence inflammatory responses and neuroimmune signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": " Collectively, these findings underscore the broad physiological relevance of miR‐451a—from its unique biogenesis to its capacity to modulate critical signaling networks in both cancer and systemic diseases—thereby offering new avenues for biomarker development and therapeutic intervention.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jr-Shiuan Yang, Thomas Maurin, Nicolas Robine, et al. 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