收稿日期: 2025-07-27
录用日期: 2025-10-13
网络出版日期: 2025-12-19
基金资助
国家重点研发计划(2021YFA1302500);国家自然科学基金(U23A20396,82270252)
Advances in metabolic modulators as therapeutic agents for heart failure
Received date: 2025-07-27
Accepted date: 2025-10-13
Online published: 2025-12-19
Supported by
National Key Research and Development Program of China(2021YFA1302500);National Natural Science Foundation of China(U23A20396,82270252)
心力衰竭（心衰）是心脏结构和功能异常导致的心输出量减少，不能满足机体代谢需求的一组复杂临床综合征。心肌能量代谢的改变是心衰的标志性事件之一，表现为能量底物利用改变、线粒体功能障碍及氧化应激加剧等特征，该变化在心衰进展中起关键作用。鉴于代谢机制对维持心脏功能的核心作用，靶向调节代谢通路的药物，即代谢调节药物，已成为极具前景的心衰治疗策略。脂肪酸氧化抑制剂（如哌克昔林）通过抑制肉碱棕榈酰转移酶Ⅰ/Ⅱ（carnitine palmitoyltransferase Ⅰ/Ⅱ，CPT1/2）减少脂肪酸β氧化，增强心脏能量代谢；3-酮脂酰辅酶A硫解酶（3-ketoacyl-coenzyme A thiolase，3-KAT）抑制剂（如曲美他嗪）可促进葡萄糖氧化，增强心肌能量供应；钠-葡萄糖协同转运蛋白2（sodium-glucose cotransporter 2，SGLT2）抑制剂（如恩格列净）除降糖作用外，还能通过多重机制改善心衰预后，但其确切的代谢机制仍需深入探索。此外，线粒体靶向肽（如伊拉米肽）通过稳定心磷脂、增强线粒体功能发挥心脏保护作用。尽管部分代谢调节药物已在临床前模型和早期临床试验中显示出潜力，但其长期疗效和安全性仍需大规模研究验证。该文综述心衰代谢调节药物的研究进展，旨在为心衰的基础研究探索和临床治疗转化提供借鉴。
杜泰来 , 黄展鹏 . 心力衰竭代谢调节药物的研究进展[J]. 上海交通大学学报（医学版）, 2025 , 45(12) : 1636 -1643 . DOI: 10.3969/j.issn.1674-8115.2025.12.009
Heart failure is a complex clinical syndrome resulting from structural and functional impairments of the heart, leading to diminished cardiac output and an inability to fulfill the body's metabolic requirements. Perturbations in myocardial energy metabolism represent a central hallmark of heart failure, characterized by altered substrate utilization, mitochondrial dysfunction, and elevated oxidative stress, all of which contribute critically to disease progression. Given the fundamental role of metabolic homeostasis in sustaining cardiac performance, pharmacological agents that target metabolic pathways, collectively termed metabolic modulators, have gained prominence as promising therapeutic strategies for heart failure. For instance, fatty acid oxidation inhibitors such as perhexiline act by suppressing carnitine palmitoyltransferase Ⅰ/Ⅱ (CPT1/2), thereby reducing fatty acid β-oxidation and improving the efficiency of cardiac energy metabolism. Similarly, 3-ketoacyl-coenzyme A thiolase (3-KAT) inhibitors, such as trimetazidine, enhance glucose oxidation, thereby improving myocardial energy supply. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., empagliflozin) not only exert hypoglycemic effects but also confer cardioprotective benefits through pleiotropic mechanisms, although their detailed metabolic actions remain under investigation. Furthermore, mitochondrial-targeting peptides, such as elamipretide, preserve mitochondrial integrity and function by stabilizating cardiolipin, thereby providing additional cardioprotection. Although several metabolic modulators have demonstrated encouraging results in preclinical and early clinical studies, their long-term efficacy and safety profiles await validation in large-scale randomized trials. This review synthesizes recent advances in the development of metabolic modulators for heart failure, providing insights into basic research and the translation of clinical treatments.
Key words： heart failure; energy metabolism; mitochondria; pharmacotherapy
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