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<p>Diacylglycerol kinases (DGKs) are crucial lipid-signaling enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA) through phosphorylation. This reaction modulates the DAG–PA axis, which is central to signal transduction, metabolic homeostasis, and immune responses. Mammals express ten DGK isoforms, classified into five subtypes on the basis of their structural features. These isoforms exhibit subtype-specific characteristics and distinct subcellular localization patterns, underpinning their diverse physiological functions. Accumulating evidence implicates DGKs in the pathogenesis of metabolic disorders, cancer, and cardiovascular and neurological diseases, where they may play either pathogenic or protective roles depending on the cellular context. This isoform-specific functionality renders DGKs promising yet underexploited therapeutic targets. Notably, one DGKζ inhibitor (ASP1570) has entered clinical trials, while other candidates, such as DGKα inhibitors (e.g., CU-3), remain at the preclinical stage. This review systematically summarizes the structural classification, catalytic mechanisms, and pathological roles of DGKs, with a particular emphasis on therapeutic targeting strategies and the associated technical challenges.</p>

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DGKs in lipid signaling and disease intervention: structural basis, pathological mechanisms, and emerging therapeutic strategies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • Jifeng Liu,
  • Jingyuan Ma,
  • Yunshu Zhang,
  • Junchen Li,
  • Yao Yang,
  • Peiyuan Yin,
  • Xing Wan,
  • Shurong Ma,
  • Dong Shang

摘要

Diacylglycerol kinases (DGKs) are crucial lipid-signaling enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA) through phosphorylation. This reaction modulates the DAG–PA axis, which is central to signal transduction, metabolic homeostasis, and immune responses. Mammals express ten DGK isoforms, classified into five subtypes on the basis of their structural features. These isoforms exhibit subtype-specific characteristics and distinct subcellular localization patterns, underpinning their diverse physiological functions. Accumulating evidence implicates DGKs in the pathogenesis of metabolic disorders, cancer, and cardiovascular and neurological diseases, where they may play either pathogenic or protective roles depending on the cellular context. This isoform-specific functionality renders DGKs promising yet underexploited therapeutic targets. Notably, one DGKζ inhibitor (ASP1570) has entered clinical trials, while other candidates, such as DGKα inhibitors (e.g., CU-3), remain at the preclinical stage. This review systematically summarizes the structural classification, catalytic mechanisms, and pathological roles of DGKs, with a particular emphasis on therapeutic targeting strategies and the associated technical challenges.