# 4-HNE-induced cellular dysfunction from lipid peroxidation: a potential therapeutic target in diabetic cardiomyopathy

## TL;DR

This paper explores how 4-HNE, a product of lipid peroxidation, contributes to diabetic cardiomyopathy and suggests potential therapeutic strategies to target its harmful effects.

## Contribution

The paper highlights the role of 4-HNE in disrupting organelle function and proposes novel therapeutic targets for diabetic cardiomyopathy.

## Key findings

- 4-HNE disrupts mitochondrial, endoplasmic reticulum, and lysosomal functions in diabetic cardiomyopathy.
- Therapeutic strategies like ALDH2 activators and ferroptosis inhibitors show potential for targeting 4-HNE effects.
- 4-HNE contributes to energy depletion, calcium overload, and autophagic flux blockade in cardiomyocytes.

## Abstract

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.