Procyanidin Capsules Combat ALF by Restoring Mitochondrial Homeostasis and Inhibiting Necroptosis via the PGAM5/DRP1/PINK1 Pathway

作者：Qing Shi, Minmin Wu, Jinwei Zhong, Chao Chen, Zhuang Huang, Jingxuan Peng, Dong Yang, Xingjie Zan, Zhengfei Wang · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202508742 · 被引用次数：5 · 研究领域：Liver physiology and pathology、Organ Transplantation Techniques and Outcomes、Mitochondrial Function and Pathology

Acute liver failure (ALF) is a life-threatening, multifactorial condition characterized by rapid progression, extensive hepatocellular necrosis, and high mortality rates. Current therapeutic options, including artificial liver support systems (ALSS) and liver transplantation, are limited by high costs, donor shortages, and insufficient efficacy. Mitochondrial dysfunction and necrotic cell death play central roles in both acute and chronic liver injury; however, their contribution to ALF remains poorly understood. In this study, self-assembled procyanidin capsules (PC-Ca) are developed with sustained antioxidant and anti-inflammatory properties that selectively accumulate in the liver of an ALF model. These findings demonstrate that PC-Ca significantly improves survival rates and more effectively mitigates liver injury, inflammation, and necrosis in thioacetamide (TAA)-induced ALF in mice and rabbits than the standard clinical agent, N-acetylcysteine (NAC). This protective effect is mediated through enhanced oxidative stress defense via activation of the KEAP1-NRF2 axis and inhibition of necroptosis via the RIPK1/RIPK3/MLKL pathway. In addition, PC-Ca preserves mitochondrial morphology and function via the PGAM5/DRP1/PINK1 pathway, offering hepatoprotection. These findings suggest that PC-Ca represents a promising therapeutic strategy for ALF, with the modulation of mitochondrial homeostasis offering valuable insights for the development of next-generation pharmacological inte...