{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Diacylglycerol kinase ε (DGKε), encoded by the DGKE gene, is a lipid kinase that phosphorylates diacylglycerol (DAG) to phosphatidic acid and thereby plays a critical role in regulating intracellular lipid signaling and the phosphatidylinositol cycle. Notably, DGKε displays exquisite substrate specificity for DAG species bearing an arachidonoyl chain at the sn‐2 position—a property that is dictated by unique structural motifs including a hydrophobic membrane‐anchoring segment, a LOX‐like motif, and an adjacent cholesterol recognition domain."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " By curtailing excessive DAG signaling—which would otherwise promote protein kinase C activation—DGKε helps to maintain a balanced pro‐ and anti‐thrombotic state. \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In several genetic studies, loss‐of‐function mutations in DGKE have been robustly associated with early‐onset renal disorders such as atypical hemolytic uremic syndrome (aHUS) and membranoproliferative-like glomerular microangiopathy, disorders that manifest with microangiopathic hemolytic anemia, thrombocytopenia, and progressive kidney injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": " Functional work in endothelial cells shows that DGKε deficiency impairs vascular endothelial growth factor receptor 2 (VEGFR2) signaling and reduces prostaglandin E₂ synthesis, thereby favoring endothelial dysfunction, defective repair, and thrombosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its well‐established role in renal and vascular biology, DGKε has been implicated in other physiologic and pathologic processes. For example, cardiac studies demonstrate that DGKε overexpression can counteract pressure overload–induced hypertrophy"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", while metabolic investigations reveal that loss of DGKε alters lipid turnover and promotes adaptations in skeletal muscle energy and glucose homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In the nervous system, DGKε modulates synaptic activity and epileptogenesis by controlling arachidonoyl-DAG levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Complementing these mechanistic insights, biochemical purification and structural analyses have confirmed that both full-length and truncated forms of DGKε retain their acyl-chain specificity and proper membrane association."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, clinical case studies document that pathogenic DGKE variants underlie a spectrum of kidney diseases—from early-onset nephropathy to steroid-resistant nephrotic syndrome—highlighting the enzyme’s central role in glomerular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Collectively, these findings underscore that DGKε is a multifaceted regulator whose function spans vascular, renal, cardiac, metabolic, and neurological tissues, making it a promising target for therapeutic intervention in DGKE-associated pathologies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael Lung, Yulia V Shulga, Pavlina T Ivanova, et al. 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