GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE332nnn/GSE332974/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332974GEOGSEfalseNon-enzymatic hepatic ABHD6 interacts with Akt-FoxO1 axis to regulate metabolic healthThe enzymatic function of ABHD6 on insulin secretion and insulin resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) is completely unexplored. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific overexpression of native and enzymatic inactive mutant ABHD6 mouse models. We demonstrated that non-enzymatic ABHD6 is an unidentified regulator of selective hepatic insulin resistance and contributes to MASLD progression. Mechanistically, we found that ABHD6 located in the nucleus and interacted with Akt/FoxO1 axis to regulate insulin signaling. Our study reveals an entirely different mechanism underlying selective hepatic insulin resistance that involves a previously unknown non-enzymatic function of ABHD6. This study opens an avenue for the development of a novel class of ABHD6 inhibitors to improve metabolic health.2026/05/26GSE332974GSM9756349GSM9756350GSM9756351GSM9756343GSM9756344GSM9756352GSM9756353GSM9756342GSM9756347GSM9756348GSM9756345GSM975634634290332974Mus musculus