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Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Neonatal liver-derived FTH1-enriched extracellular vesicles attenuate ferroptosis and ameliorate MASLD pathogenesis
Xin Zeng1, Wei Jiang2, Tian Wu3
1Department of Liver Transplantation Center and National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
Metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver pathology, lacks effective therapies. This study identifies ferroptosis-a lipid peroxidation-driven, iron-dependent form of cell death-as a central pathogenic mechanism in MASLD. Integrative proteomic and histopathological analyses of human and murine MASLD livers revealed marked ferroptosis activation, characterized by dysregulated iron metabolism (reduced FTH1 and GPX4; elevated ACSL4) and oxidative stress. To address this, neonatal liver-derived extracellular vesicles (EVnew) enriched with FTH1, were evaluated as a therapeutic strategy. EVnew exhibited superior biodistribution to adult-derived EVs (EVadult), with liver-specific tropism and proteomic enrichment of FTH1, mitochondrial proteins, and glutathione regulators. In MASLD models, EVnew administration attenuated hepatic injury, steatosis, and fibrosis, outperforming EVadult by restoring iron homeostasis via FTH1-mediated suppression of lipid peroxidation. Specifically, EVnew upregulated NRF2 and GPX4 while downregulating ACSL4 and HSP60. Neutralizing FTH1 abolished the protective effects of EVnew in vitro, confirming that FTH1 is the key mediator. These findings establish ferroptosis as a therapeutic target in MASLD and highlight the dual capacity of EVnew to inhibit ferroptosis. This work pioneers xenogeneic EVs-based therapy for metabolic liver diseases, offering a novel multifaceted intervention with translational potential.
Insights
Ferroptosis drives metabolic dysfunction-associated steatotic liver disease (MASLD). Neonatal extracellular vesicles (EVnew) containing FTH1 show promise in treating MASLD by inhibiting ferroptosis and restoring iron homeostasis.
Area of Science:
- Hepatology
- Cell Death Research
- Extracellular Vesicle Biology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of chronic liver disease with limited therapeutic options.
- Ferroptosis, a form of cell death driven by lipid peroxidation and iron, is implicated in MASLD pathogenesis.
Purpose of the Study:
- To investigate ferroptosis as a key mechanism in MASLD.
- To evaluate neonatal liver-derived extracellular vesicles (EVnew) as a potential therapy for MASLD.
Main Methods:
- Integrative proteomic and histopathological analyses of human and murine MASLD liver samples.
- Administration of EVnew and adult-derived EVs (EVadult) in MASLD models.
- In vitro studies involving FTH1 neutralization.
Main Results:
- MASLD livers showed significant ferroptosis activation with dysregulated iron metabolism (reduced FTH1, GPX4; elevated ACSL4).
- EVnew demonstrated superior liver-specific biodistribution and attenuated hepatic injury, steatosis, and fibrosis in MASLD models.
- EVnew restored iron homeostasis by upregulating FTH1, NRF2, and GPX4, while downregulating ACSL4 and HSP60, thereby suppressing lipid peroxidation.
Conclusions:
- Ferroptosis is a critical therapeutic target for MASLD.
- EVnew effectively inhibits ferroptosis and shows therapeutic potential for metabolic liver diseases.
- This study pioneers xenogeneic extracellular vesicle-based therapy for MASLD, offering a novel treatment strategy.
