Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria, allowing for adjustments in cellular energy metabolism to maintain metabolic homeostasis. Small molecule uncouplers have been extensively studied for their potential to increase metabolic rate, and recent research has focused on developing safe and effective mitochondrial uncoupling agents for the treatment of obesity and cardiometabolic syndrome (CMS). Here, we provide a brief overview of CMS and cover the recent mechanisms by which chemical uncouplers regulate CMS-associated risk-factors and comorbidities, including dyslipidemia, insulin resistance, steatotic liver disease, type 2 diabetes, and atherosclerosis. Additionally, we review the current landscape of uncoupling agents, focusing on repurposed FDA-approved drugs and compounds in advanced preclinical or early-stage clinical development. Lastly, we discuss recent molecular insights by which chemical uncouplers enhance cellular energy expenditure, highlighting their potential as a new addition to the current CMS drug landscape, and outline several limitations that need to be addressed before these agents can successfully be introduced into clinical practice.

中文翻译：

---

心脏代谢综合征中线粒体解偶联的生化基础和治疗潜力。


氧化磷酸化的温和解偶联是所有线粒体的固有特性，允许调整细胞能量代谢以维持代谢稳态。小分子解偶联剂因其提高代谢率的潜力而被广泛研究，最近的研究集中在开发安全有效的线粒体解偶联剂来治疗肥胖和心脏代谢综合征 （CMS）。在这里，我们简要概述了 CMS，并涵盖了化学解偶联剂调节 CMS 相关风险因素和合并症的最新机制，包括血脂异常、胰岛素抵抗、脂肪性肝病、2 型糖尿病和动脉粥样硬化。此外，我们还回顾了解偶联剂的现状，重点关注 FDA 批准的重新利用的药物和化合物在晚期临床前或早期临床开发中的作用。最后，我们讨论了化学解偶联剂增加细胞能量消耗的最新分子见解，强调了它们作为当前 CMS 药物格局新成员的潜力，并概述了在这些药物成功引入临床实践之前需要解决的几个限制。