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Targeting ferroptosis by poly(acrylic) acid coated Mn3O4 nanoparticles alleviates acute liver injury
Xinyi Shan1,2, Jiahuan Li1,2, Jiahao Liu2,3,4
1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
Abstract:
Ferroptosis, a newly characterized form of regulated cell death, is induced by excessive accumulation of lipid peroxidation catalyzed by intracellular bioactive iron. Increasing evidence has suggested that ferroptosis is involved in the pathogenesis of several human diseases, including acute liver injury. Targeted inhibition of ferroptosis holds great promise for the clinical treatment of these diseases. Herein, we report a simple and one-pot synthesis of ultrasmall poly(acrylic) acid coated Mn3O4 nanoparticles (PAA@Mn3O4-NPs, PMO), which perform multiple antioxidant enzyme-mimicking activities and can scavenge broad-spectrum reactive oxygen species. PMO could potently suppress ferroptosis. Mechanistically, after being absorbed mainly through macropinocytosis, PMO are largely enriched in lysosomes, where PMO detoxify ROS, inhibit ferritinophagy-mediated iron mobilization and preserve mTOR activation, which collectively confer the prominent inhibition of ferroptosis. Additionally, PMO injection potently counteracts lipid peroxidation and alleviates acetaminophen- and ischaemia/reperfusion-induced acute liver injury in mice. Collectively, our results reveal that biocompatible PMO act as potent ferroptosis inhibitors through multifaceted mechanisms, which ensures that PMO have great translational potential for the clinical treatment of ferroptosis-related acute liver injury.
Insights
Poly(acrylic) acid coated Mn3O4 nanoparticles (PMO) effectively inhibit ferroptosis, a cell death pathway implicated in liver injury. These nanoparticles scavenge reactive oxygen species and protect against liver damage in mice.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cell Biology
Background:
- Ferroptosis is a regulated cell death pathway driven by iron-catalyzed lipid peroxidation.
- Ferroptosis plays a role in acute liver injury pathogenesis.
- Targeting ferroptosis offers therapeutic potential for liver diseases.
Purpose of the Study:
- To synthesize and characterize poly(acrylic) acid coated Mn3O4 nanoparticles (PMO) with antioxidant properties.
- To investigate the ferroptosis inhibitory mechanisms of PMO.
- To evaluate the therapeutic efficacy of PMO in mouse models of acute liver injury.
Main Methods:
- One-pot synthesis of ultrasmall poly(acrylic) acid coated Mn3O4 nanoparticles (PMO).
- In vitro assessment of ROS scavenging and antioxidant enzyme-mimicking activities.
- Macropinocytosis uptake and lysosomal localization studies.
- In vivo evaluation of PMO in acetaminophen- and ischemia/reperfusion-induced acute liver injury mouse models.
Main Results:
- PMO demonstrated broad-spectrum reactive oxygen species scavenging and antioxidant enzyme-mimicking activities.
- PMO were efficiently internalized via macropinocytosis and localized in lysosomes.
- PMO inhibited ferroptosis by detoxifying ROS, blocking iron release from ferritinophagy, and maintaining mTOR activation.
- PMO injection significantly alleviated liver injury in mouse models.
Conclusions:
- Biocompatible PMO act as potent ferroptosis inhibitors through multiple mechanisms.
- PMO show significant therapeutic potential for treating ferroptosis-related acute liver injury.
