{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRRM2 (ribonucleotide reductase subunit M2) is an indispensable component of the ribonucleotide reductase enzyme responsible for reducing ribonucleotides to deoxyribonucleotides—a rate‐limiting step that supplies the balanced dNTP pools essential for DNA replication and repair. Several studies have delineated how proper RRM2 function is critical for both replicative and repair DNA synthesis, with its activity directly impacting genome stability and the cell’s capacity to cope with DNA damage and replication stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRRM2 levels are subject to strict regulation by cell cycle checkpoints and DNA damage response pathways. Its abundance is modulated via post‐translational mechanisms—such as cyclin-dependent kinase phosphorylation followed by cyclin F–mediated ubiquitin degradation—and through transcriptional control by factors including E2F1, p21, and p53 family members. Additionally, signaling cascades like the ATR–Chk1 pathway have been implicated in stimulating RRM2 expression under genotoxic stress, ensuring that adequate dNTPs are available for repair processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant expression of RRM2 is a common hallmark in a variety of malignancies where its overexpression or gene amplification not only boosts the intracellular dNTP pool to favor DNA synthesis but also contributes to aggressive tumor behavior, metastasis, and chemoresistance. Elevated RRM2 levels have been associated with enhanced cell proliferation and invasive properties in cancers including those of the breast, lung, pancreas, prostate, gastric tissues, and renal cells. Moreover, RRM2 can modulate critical oncogenic signaling pathways (such as NF‑κB and AKT) that further potentiate malignant transformation and resistance to therapeutic agents like gemcitabine."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOwing to its central role in sustaining DNA synthesis and repair as well as promoting tumor aggressiveness, RRM2 has emerged as a valuable prognostic biomarker and a promising therapeutic target. Intervention strategies—including RNA interference, small molecule inhibitors, and the modulation of regulatory RNAs (such as microRNAs and piRNAs)—have shown that RRM2 downregulation can sensitize cancer cells to chemotherapeutics, reverse drug resistance, and inhibit tumor growth in preclinical models. These innovative approaches underscore the potential of targeting RRM2 to improve treatment responses and clinical outcomes across a spectrum of malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lijun Xue, Bingsen Zhou, Xiyong Liu, et al. 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