{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nA series of studies have demonstrated that pyruvate dehydrogenase kinases (PDKs) are central metabolic regulators that control the conversion of pyruvate to acetyl‐CoA through phosphorylation of the pyruvate dehydrogenase complex. These investigations span diverse cellular systems – from hematopoietic stem cells maintaining quiescence (via a glycolytic, PDK‐dependent mechanism) to cancer cells where wild‐type p53 suppresses the Warburg effect by down‐regulating PDK2, and even extend to analyses in head and neck cancers, skeletal muscle metabolism, and oocyte maturation. Collectively, these works reveal that modulation of PDK isoforms (such as PDK2, PDK4 and others) reprograms cellular metabolic fluxes to impact bioenergetics, cell proliferation, differentiation, and stress responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOther studies in the compilation have further linked PDK activity to pathophysiological processes including painful diabetic neuropathy, inflammatory pain, liver steatosis in diabetes, impaired macrophage polarization, abnormal osteoclast activation in osteoporosis, dysregulated adipogenesis in obesity, and detrimental inflammatory responses in endotoxin shock. These findings underscore the concept that distinct PDK isoenzymes not only serve as metabolic checkpoints but also as potential therapeutic targets across a wide range of disease models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNotably, although the compiled abstracts provide a rich perspective on metabolic reprogramming and the multifaceted roles of PDK isoenzymes in modulating energy balance, cell fate, and inflammatory responses, none of these reports mention or analyze OBSCN-AS1. As a result, while these studies illuminate critical metabolic checkpoints, they do not offer any insights into the function or regulatory potential of OBSCN-AS1. Further investigation will be necessary to determine whether OBSCN-AS1 plays a role in any of these PDK‐mediated metabolic processes.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wenyue Sun, Shaoyu Zhou, Steven S Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial mutations contribute to HIF1alpha accumulation via increased reactive oxygen species and up-regulated pyruvate dehydrogenease kinase 2 in head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-08-0930"}], "href": "https://doi.org/10.1158/1078-0432.CCR-08-0930"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19147752"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19147752"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Emily C Dunford, Eric A Herbst, Nam Ho Jeoung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice: effect of PDH kinase 1 compensation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Regul Integr Comp Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpregu.00498.2010"}], "href": "https://doi.org/10.1152/ajpregu.00498.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21411764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21411764"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tanupriya Contractor, Chris R Harris "}, {"type": "b", "children": [{"type": "t", "text": "p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-11-1215"}], "href": "https://doi.org/10.1158/0008-5472.CAN-11-1215"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22123926"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22123926"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Keiyo Takubo, Go Nagamatsu, Chiharu I Kobayashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2012.10.011"}], "href": "https://doi.org/10.1016/j.stem.2012.10.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23290136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23290136"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rongya Tao, Xiwen Xiong, Robert A Harris, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0071997"}], "href": "https://doi.org/10.1371/journal.pone.0071997"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23940800"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23940800"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shih-Chia Tso, Xiangbing Qi, Wen-Jun Gui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.533885"}], "href": "https://doi.org/10.1074/jbc.M113.533885"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24356970"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24356970"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yasmeen Rahimi, João-Paulo G Camporez, Max C Petersen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1419104111"}], "href": "https://doi.org/10.1073/pnas.1419104111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25368185"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25368185"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xiaojing Hou, Liang Zhang, Longsen Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differing roles of pyruvate dehydrogenase kinases during mouse oocyte maturation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.167049"}], "href": "https://doi.org/10.1242/jcs.167049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25991547"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25991547"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Md Habibur Rahman, Mithilesh Kumar Jha, Jong-Heon Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.699215"}], "href": "https://doi.org/10.1074/jbc.M115.699215"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26769971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26769971"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mithilesh Kumar Jha, Md Habibur Rahman, Dong Ho Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pyruvate dehydrogenase kinase 2 and 4 gene deficiency attenuates nociceptive behaviors in a mouse model of acute inflammatory pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jnr.23727"}], "href": "https://doi.org/10.1002/jnr.23727"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26931482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26931482"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Younghoon Go, Ji Yun Jeong, Nam Ho Jeoung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of Pyruvate Dehydrogenase Kinase 2 Protects Against Hepatic Steatosis Through Modulation of Tricarboxylic Acid Cycle Anaplerosis and Ketogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db16-0223"}], "href": "https://doi.org/10.2337/db16-0223"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27385159"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27385159"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Byong-Keol Min, Sungmi Park, Hyeon-Ji Kang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2019.00944"}], "href": "https://doi.org/10.3389/fimmu.2019.00944"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31134063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31134063"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Ji-Min Lee, Min-Ji Kim, Sun Joo Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PDK2 Deficiency Prevents Ovariectomy-Induced Bone Loss in Mice by Regulating the RANKL-NFATc1 Pathway During Osteoclastogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.4202"}], "href": "https://doi.org/10.1002/jbmr.4202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33125772"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33125772"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Hyeon-Ji Kang, Byong-Keol Min, Won-Il Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pyruvate dehydrogenase kinase 1 and 2 deficiency reduces high-fat diet-induced hypertrophic obesity and inhibits the differentiation of preadipocytes into mature adipocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Mol Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s12276-021-00672-1"}], "href": "https://doi.org/10.1038/s12276-021-00672-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34552205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34552205"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Chunxia Li, Jun Dai, Chuanbin Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pyruvate Dehydrogenase Kinase 2 Accelerates Endotoxin Shock by Promoting Mitogen-Activated Protein Kinase Activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Inflammation (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10753-022-01744-8"}], "href": "https://doi.org/10.1007/s10753-022-01744-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36171490"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36171490"}]}]}]}