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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\u2010assembled procyanidin capsules (PC\u2010Ca) are developed with sustained antioxidant and anti\u2010inflammatory properties that selectively accumulate in the liver of an ALF model. These findings demonstrate that PC\u2010Ca significantly improves survival rates and more effectively mitigates liver injury, inflammation, and necrosis in thioacetamide (TAA)\u2010induced ALF in mice and rabbits than the standard clinical agent, N\u2010acetylcysteine (NAC). This protective effect is mediated through enhanced oxidative stress defense via activation of the KEAP1\u2010NRF2 axis and inhibition of necroptosis via the RIPK1\/RIPK3\/MLKL pathway. In addition, PC\u2010Ca preserves mitochondrial morphology and function via the PGAM5\/DRP1\/PINK1 pathway, offering hepatoprotection. These findings suggest that PC\u2010Ca represents a promising therapeutic strategy for ALF, with the modulation of mitochondrial homeostasis offering valuable insights for the development of next\u2010generation pharmacological interventions.<\/jats:p>","DOI":"10.1002\/advs.202508742","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T05:44:47Z","timestamp":1764827087000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Procyanidin Capsules Combat ALF by Restoring Mitochondrial Homeostasis and Inhibiting Necroptosis via the PGAM5\/DRP1\/PINK1 Pathway"],"prefix":"10.1002","volume":"13","author":[{"given":"Qing","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou 325035 China"},{"name":"Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation The First 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