REVIEW article
Front. Cell Dev. Biol.
Sec. Cellular Biochemistry
This article is part of the Research TopicCellular Organelle Dynamic Remodelling in Metabolic DiseasesView all articles
4-HNE-Induced Cellular Dysfunction from Lipid Peroxidation: A Potential Therapeutic Target in Diabetic Cardiomyopathy
Provisionally accepted
- 1Second People’s Hospital of Zhoushan, Zhoushan, China
- 2Other
- 3Heilongjiang University of Chinese Medicine Affiliated Second Hospital, Harbin, China
- 4Heilongjiang University of Chinese Medicine, Harbin, China
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Diabetic cardiomyopathy (DCM) is one of the crucial causes leading to heart failure and adverse outcomes in patients with diabetes mellitus; however, effective strategies targeting its molecular pathological mechanisms and therapies are currently lacking. DCM is primarily characterized by early diastolic dysfunction, cardiomyocyte apoptosis, and fibrosis. Its disease progression is relatively insidious, eventually evolving into heart failure with preserved ejection fraction. The intrinsic metabolic environment of diabetes markedly exacerbates oxidative stress, and the accumulated polyunsaturated fatty acids within cardiomyocytes are highly susceptible to lipid peroxidation, leading to the excessive generation of 4-hydroxy-2-nonenal (4-HNE). The pivotal role of this reactive aldehyde in promoting the progression of DCM has been extensively demonstrated in animal, cellular, and clinical models. However, its subcellular targets and the underlying molecular mechanisms remain inadequately elucidated. Organelles, as central executors of diverse intracellular functions, may serve as potential sites of 4-HNE-induced interference and therapeutic targeting. This article focuses on the central role of 4-HNE in triggering energy depletion, calcium overload, autophagic flux blockade, and ferroptosis through its interactions among mitochondria, endoplasmic reticulum, lysosomes, and other organelles. On the basis of existing evidence, potentially translatable therapeutic avenues include ALDH2 activators, G protein – coupled receptor 40 (GPR40) agonists, mitochondria-targeted antioxidants and ferroptosis inhibitors. The aim is to provide a theoretical foundation and reference for the clinical identification of myocardial injury in DCM, model replication, and the development of targeted intervention strategies.
Keywords: Diabetic cardiomyopathy, 4-HNE, Oxidative Stress, Lipid Peroxidation, Organelles
Received: 10 Jul 2025; Accepted: 04 Dec 2025.
Copyright: © 2025 Jiang, Ma, Chen and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Huijun Chen
Chengjia Li
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