# Angelica sinensis polysaccharide nanoparticles can improve myocardial ischemia-reperfusion injury by inhibiting ferritinophagy via the ATF6/NCOA4 pathway

## TL;DR

Angelica sinensis polysaccharide nanoparticles protect heart cells from injury by blocking a process called ferritinophagy, which helps reduce harmful effects of iron and oxygen stress.

## Contribution

ASP@PLGA-PEG nanoparticles are shown to inhibit ferritinophagy via the ATF6/NCOA4 pathway, offering a novel strategy for treating myocardial ischemia-reperfusion injury.

## Key findings

- ASP@PLGA-PEG nanoparticles reduced oxidative stress and improved cell viability in injured cardiomyocytes.
- Treatment with ASP@PLGA-PEG preserved cardiac function and reduced infarct size in both ex vivo and in vivo models.
- The protective effects of ASP@PLGA-PEG were found to be critically dependent on ATF6 signaling.

## Abstract

Ferroptosis aggravates myocardial ischemia-reperfusion injury (MI/RI) by disrupting iron homeostasis, accelerating lipid peroxidation, and elevating reactive oxygen species (ROS) levels. Although Angelica sinensis polysaccharide (ASP) has shown protective effects against MI/RI, its clinical translation remains limited due to poor bioavailability and low target specificity.

To address these limitations, we developed ASP@PLGA-PEG nanoparticles using a solvent evaporation method and characterized their morphology, size distribution, and surface charge by transmission electron microscopy, dynamic light scattering, and zeta potential analysis. The protective effects of ASP@PLGA-PEG were first evaluated in HL-1 cardiomyocytes subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) by assessing cell viability, mitochondrial membrane potential, ROS generation, lipid peroxidation, and antioxidant capacity. An ex vivo MI/RI model was then established using a Langendorff isolated heart perfusion system to assess hemodynamic function, infarct size, histopathology, and mitochondrial ultrastructure. In addition, an in vivo mouse MI/R model induced by LAD ligation–reperfusion was used to evaluate cardiac function, infarct size, serum injury markers, oxidative stress, and ferroptosis-/ER stress–related proteins. Finally, siRNA-mediated ATF6 knockdown was performed in HL-1 cells to determine whether the protective and anti-ferroptotic effects of ASP@PLGA-PEG are ATF6 dependent.

ASP@PLGA-PEGnanoparticles significantly reduced oxidative stress, improved cardiomyocyteviability, and inhibited ferroptosis in OGD/R-injured HL-1 cells. In theLangendorff model, ASP@PLGA-PEG treatment effectively decreased myocardialinfarct size, preserved cardiac hemodynamics, and alleviated structural damage.Consistently, in vivo administration of ASP@PLGA-PEG markedly improved leftventricular systolic function, reduced infarct size and serum LDH levels, preserved mitochondrial and histologicalintegrity, and restored redox homeostasis in MI/R hearts. Mechanistically,ASP@PLGA-PEG nanoparticles activated ATF6 signaling and attenuated ER stress,while suppressing NCOA4-mediated ferritinophagy, thereby limiting iron overloadand lipid peroxidation to protect cardiomyocytes against ferroptosis duringMI/RI. Importantly, ATF6 knockdown largely abrogated the effects ofASP@PLGA-PEG on NCOA4/FTH1 expression, ROS production, and lipid peroxidation,indicating that these protective actions are critically ATF6 dependent.

Thisstudy demonstrates that ASP@PLGA-PEG nanoparticles exert potentcardioprotective effects in vitro, ex vivo, and in vivo through a multi-targetmechanism involving ER stress modulation, enhancement of antioxidativedefenses, and inhibition of ferritinophagy-driven ferroptosis. These findingshighlight ASP@PLGA-PEG as a promising nanomedicine strategy for the preventionand treatment of myocardial ischemia–reperfusion injury.

The online version contains supplementary material available at 10.1186/s12967-026-07752-8.