{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIK3R3, a regulatory subunit of class IA phosphoinositide 3‐kinases, is emerging as a multifunctional mediator of oncogenic signaling. In numerous cancer models—including non–small‐cell lung cancer, glioblastoma, colorectal cancer, triple‐negative breast cancer, and pancreatic cancer—upregulation of PIK3R3 has been linked to enhanced cell proliferation, migration, invasion, and epithelial–mesenchymal transition. This oncogenic drive is largely due to its ability to modulate key downstream effectors such as the AKT/mTOR and NF‐κB pathways, thereby facilitating tumor metastasis and chemoresistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPIK3R3 expression and activity are subject to complex upstream regulation by microRNAs, transcription factors, genetic polymorphisms, and epigenetic modifications. Several reports have shown that microRNAs—including miR-148b, miR-511, miR-193a-5p, miR-224-5p, and miR-365—can directly target PIK3R3 mRNA, dampening oncogenic PI3K/AKT signaling. In addition, transcriptional regulators such as SNAI2 and elements of the TGF-β/NKX2.1 axis, as well as m^6A modification mechanisms orchestrated by von Hippel–Lindau and associated m^6A writers, have been implicated in modulating PIK3R3 expression. Genetic variants within its promoter region further influence its transcriptional activity and have been associated with altered cancer risk and clinical outcomes in contexts such as gastric, colorectal, and hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer, PIK3R3 is also involved in nonmalignant processes such as cell cycle progression, inflammatory regulation, metabolic homeostasis, and tissue injury responses. Experimental systems have demonstrated that modulation of PIK3R3 affects endothelial cell function in diabetic foot ulcers, hepatic fatty acid oxidation in nonalcoholic fatty liver disease, as well as vascular smooth muscle cell proliferation in lung disorders and emphysema models. In neuronal and hematologic contexts, alterations in PIK3R3 expression—either via targeted peptides or microRNA-mediated mechanisms—impact apoptosis, differentiation, and inflammatory cytokine release, highlighting its potential as a therapeutic target across a spectrum of disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Liliana Soroceanu, Samir Kharbanda, Ruihuan Chen, et al. 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