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  3. Neonatal Liver-Derived Extracellular Vesicle: Unlocking Mitochondrial Repair and Regenerative Mechanisms in Alcoholic Liver Disease

Neonatal Liver-Derived Extracellular Vesicle: Unlocking Mitochondrial Repair and Regenerative Mechanisms in Alcoholic Liver Disease

  • Small. 2025 Oct 25:e09351. doi: 10.1002/smll.202509351.
Xin Zeng 1,  Wei Jiang 2 3 4,  Shisheng Wang 5,  Liqiang Hu 6,  Yaojia Zhou 7,  Qingmin Zeng 2 3 4,  Xiong Pei 2 3 4,  Jingping Liu 1,  Qi Cao 8,  Hong Tang 2 3 4,  Dongbo Wu 2 3 4,  Chengshi Wang 9
Affiliations

Affiliations

  • 1 Center of Infectious Diseases, Department of Liver Transplantation Center and National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610000, China.
  • 2 Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China.
  • 3 Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China.
  • 4 Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 5 West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 6 West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 7 Animal experimental center of West China hospital, Sichuan University, Chengdu, 610041, China.
  • 8 Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd Westmead, Sydney, NSW, 2145, Australia.
  • 9 Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China.
PMID: 41137551 DOI: 10.1002/smll.202509351
Abstract

Alcoholic liver disease (ALD) represents a formidable global health challenge with limited effective therapeutic interventions. This study investigates the therapeutic potential and underlying mechanisms of xenogeneic neonatal liver-derived extracellular vesicles in ALD. EVneo (neonatal rat liver-derived extracellular vesicle) and EVadult (adult rat liver-derived extracellular vesicle) are isolated via differential centrifugation and rigorously characterized. A preclinical ALD mouse model is established using the National Institute on Alcohol Abuse and Alcoholism model, with comparative therapeutic assessment of intravenously administered EVneo vs EVadult. Proteomic profiling of liver tissues and EVs （extracellular vesicles）, integrated with immunohistochemical analyses, fluorescence imaging, mitochondrial functional assays, and quantification of inflammatory/regenerative markers, elucidated therapeutic mechanisms. Key findings demonstrate that EVneo-specific enrichment of mitochondrial biogenesis, anti-inflammatory, and anti-apoptotic pathways. EVneo administration significantly attenuates hepatic steatosis and inflammatory responses, restores mitochondrial homeostasis through redox balance modulation, induces macrophage polarization toward an M2 reparative phenotype, enhances hepatocyte proliferation, and suppresses apoptotic signaling. Comparative analysis revealed EVneo 's superior therapeutic efficacy over EVadult, attributable to its developmentally programmed cargo that orchestrates mitochondrial resilience, immunometabolic reprogramming, and parenchymal regeneration. These findings establish developmental stage-specific EV therapeutics as a paradigm for ALD treatment, emphasizing their multimodal mechanistic advantages in counteracting alcohol-induced hepatopathology.

Keywords

alcoholic liver disease; extracellular vesicle; liver regeneration; macrophage reprogramming; mitochondrial stress.

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