AKR1B10 drives hepatic steatosis and inflammation in metabolic dysfunction-associated steatotic liver disease via PI3K/AKT-mediated autophagy suppression.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder marked by excessive hepatic lipid accumulation, in which impaired autophagy plays a critical role. Aldo-keto reductase family 1 member B10 (AKR1B10) has been implicated in lipid metabolism; however, its regulatory function in MASLD pathogenesis remains poorly understood. This study aimed to elucidate the role of AKR1B10 in MASLD progression and the underlying molecular mechanisms. Differentially expressed genes were identified using the GSE135251 dataset. Serum and liver tissue samples were obtained from 28 patients with MASLD and 28 healthy controls. In vivo, a MASLD mouse model was established by feeding a high-fat diet (HFD), while in vitro, lipid accumulation was induced in AML-12 hepatocytes by treatment with free fatty acids (FFA). This study found that AKR1B10 expression was significantly upregulated in MASLD patients, HFD-fed mice, and FFA-treated AML-12 cells. Silencing AKR1B10 alleviated lipid accumulation, inflammation, and autophagic impairment in vitro, and attenuated hepatic steatosis and metabolic dysfunction in vivo. Mechanistically, AKR1B10 knockdown suppressed PI3K/AKT pathway activation, thereby ameliorating lipid deposition, inflammation, and autophagic dysfunction. Conversely, treatment with 740Y-P, a PI3K agonist, reversed these protective effects and exacerbated MASLD progression. Our findings demonstrates that AKR1B10 promotes MASLD progression through activation of the PI3K/AKT signaling pathway, contributing to dysregulated lipid metabolism, inflammation, and autophagy inhibition. These findings suggest that targeting AKR1B10 may represent a novel therapeutic strategy for MASLD.