{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIK3CD encodes the p110δ catalytic subunit of phosphoinositide 3‐kinase, a lipid kinase predominantly expressed in leukocytes that orchestrates key signaling pathways for lymphocyte development and function. Gain‐of‐function mutations in PIK3CD cause activated PI3Kδ syndrome (APDS), which manifests with recurrent sinopulmonary infections, lymphadenopathy, viral (CMV/EBV) viremia, and dysregulated T‐cell homeostasis marked by a loss of naïve T cells and accumulation of senescent effector cells. Hyperactivation of downstream effectors, such as AKT and mTOR, drives metabolic and functional defects in these immune cells, and targeted inhibition (for example with rapamycin or p110δ‐selective drugs) can partially restore immune cell function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn lymphocytes, PI3Kδ is indispensable for antigen receptor–mediated signaling. In T cells, its activity helps drive clonal expansion, proper Th1/Th2 differentiation, and cytokine production, while in B cells, both heightened and diminished PI3Kδ signaling can lead to defective class‑switch recombination—contributing to hyper IgM phenotypes and increased susceptibility to lymphoproliferation. In addition, transcriptional regulators such as RUNX1 modulate PIK3CD expression, influencing chemotherapy responses in acute leukemias and linking PI3Kδ activity to the oncogenic landscape observed in certain hematologic malignancies, including hepatosplenic T‑cell lymphoma and T‑cell acute lymphoblastic leukemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant PI3Kδ signaling also underpins oncogenic processes in both hematologic and solid tumors. In acute myeloid leukemia and Hodgkin lymphoma, high expression or activating mutations of PIK3CD promote cell survival and proliferation via enhanced AKT signaling; in colorectal cancer, overexpression of PIK3CD stimulates an AKT/GSK‑3β/β‑catenin cascade that drives tumor growth and invasion, a pathway further modulated by microRNAs (e.g., miR‑30a). In Ras‐driven tumors, including certain neuroblastomas, direct activation of p110δ by membrane‐resident Ras amplifies oncogenic signals. Selective PI3Kδ inhibitors—such as idelalisib and novel agents like AMG319—have shown promise in preclinical models and clinical studies by curbing these oncogenic signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond adaptive immunity and oncogenesis, PI3Kδ plays pivotal roles in innate immune responses and in mediating the effects of inflammatory signals. In neutrophils, PI3Kδ activity is essential for directional chemotaxis and contributes to the regulation of netosis in response to pathogenic challenges. Moreover, inflammatory mediators such as TNF‑α and metabolic stressors including palmitate upregulate PIK3CD expression in endothelial cells and synoviocytes, implicating PI3Kδ in the pathogenesis of rheumatoid arthritis, chronic obstructive pulmonary disease, and obesity‐associated inflammation. In addition, upstream regulatory mechanisms—including engagement of phosphatases like CD148 and the use of alternative promoter regions—ensure tight control over PI3Kδ signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carrie L Lucas, Hye Sun Kuehn, Fang Zhao, et al. 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