OTUB1 enhances fatty acid oxidation in APAP-induced liver injury by mediating ACSL5 deubiquitination.

Overdosing on acetaminophen (APAP) is the primary cause of drug-induced liver injury. Recent studies have demonstrated that dysregulated lipid metabolism, particularly decreased fatty acid oxidation (FAO), is a key contributor to APAP-induced acute liver injury (AILI). OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1), a crucial member of the OTU deubiquitinase family, has been involved in the metabolic progression of multiple diseases. Nevertheless, its involvement in AILI as well as FAO remains unclear. Here, we aimed to elucidate the effects of OTUB1 on the regulation of FAO in AILI. Our investigation revealed decreased OTUB1 expression in AILI. OTUB1 overexpression not only alleviated liver injury but also improved FAO in vivo and in vitro. Conversely, opposite biochemical changes were observed in hepatocytes with OTUB1 knockdown. Mechanistically, long-chain acyl-CoA synthase 5 (ACSL5), which plays a crucial role in regulating FAO, was identified as a novel substrate of OTUB1 in AILI via mass spectrometry analysis. OTUB1 interacts with ACSL5 and promotes its deubiquitination and stability. Moreover, the protective effect of OTUB1 on FAO in AILI occurred via the deubiquitination of ACSL5. Overall, the present study revealed that the OTUB1-ACSL5 axis plays an essential role in regulating FAO during AILI progression and might be a novel target for therapeutic intervention.