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HMGB1 is a promising therapeutic target for acute liver failure. INTRODUCTION: Although acute liver failure (ALF) is a rare disease, it continues to have high mortality and morbidity rates due to its many causes. High mobility group box 1 (HMGB1), originally reported as a ubiquitous non-histone chromosomal protein, is a multi-functional protein with varying functions depending on its location, such as in the nucleus, cytoplasm and extracellular space. The role of extracellular HMGB1 as an inflammatory mediator has been well studied, and the elevation of serum HMGB1 has been reported in several diseases that are closely associated with ALF. Areas covered: In this review, we focus on the relationship between causes of acute liver failure, such as viral infection, drug-induced liver injury, ischemia/reperfusion injury, and acute-on-chronic liver failure, and the role of HMGB1. Furthermore, we also consolidate and summarize the current reports of HMGB1-targeting therapies in hepatic injury models. Expert commentary: HMGB1 could be a novel therapeutic candidate for ALF, and the clinical testing of HMGB1-targeting therapies for ALF patients is expected.