{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPDK1 is a critical metabolic regulator that governs the balance between mitochondrial oxidation and aerobic glycolysis by phosphorylating and inactivating the pyruvate dehydrogenase complex. Under hypoxic conditions, HIF‐1α drives PDK1 expression to suppress the flow of pyruvate into the tricarboxylic acid cycle, thereby favoring glycolysis and reducing reactive oxygen species generation. This adaptive switch is observed not only in cancer cells—with HIF‐1α acting alone or in collaboration with oncogenes like c‐Myc—but also during somatic cell reprogramming where early induction of PDK1 helps establish a glycolytic program. In parallel, studies of RNA surveillance mechanisms have underscored how stress‐induced transcriptomic changes can indirectly impact metabolic regulators such as PDK1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer, overexpression of PDK1 is frequently linked to enhanced tumor cell survival, proliferation, stem‐like properties, and chemoresistance. For instance, in breast cancer stem cells and metastatic lesions, PDK1 supports glycolytic reprogramming required for growth in hypoxic microenvironments. Structural characterizations have guided the development of small‐molecule inhibitors (such as dichloroacetate and related compounds) that target specific binding pockets of PDK1, leading to decreased lactate production, induction of mitochondrial oxidative metabolism, and increased apoptotic sensitivity. Moreover, oncogenic signals—including those mediated by the Lin28/let‐7 axis as well as alterations in transcriptional regulators like KDM4A/E2F1—promote PDK1 transcription. Such deregulation is evident in various malignancies including head and neck, gastric, non‐small cell lung, and even in chemoresistant leukemia, where interfering with the PDK1 axis (often through combined targeting with other agents) has shown potential to overcome therapy resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further illustrates that PDK1 is not only a linchpin of metabolic reprogramming but also a promising prognostic marker and therapeutic target across diverse tumor types. In cholangiocarcinoma, nasopharyngeal carcinoma, colorectal cancer, melanoma, bladder cancer, and neuroblastoma, aberrant PDK1 expression—modulated by non‐coding RNAs such as lncRNAs and miRNAs (for example, via ceRNA mechanisms and direct 3′‐UTR targeting)—correlates with aggressive behavior and poor patient outcomes. In addition, studies in cardiac cells have highlighted that modulation of PDK1 by miRNAs can shift the balance from glycolysis toward mitochondrial respiration under hypoxic stress, suggesting potential broader implications in tissue injury responses. Collectively, these findings underscore the diverse roles of PDK1 in controlling metabolic flux, supporting cell survival under stress, and driving tumor progression, thereby offering multiple avenues for targeted intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jung-whan Kim, Irina Tchernyshyov, Gregg L Semenza, et al. 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