FTO-mediated regulation of Kupffer cell polarization and interleukin-6 secretion promotes biliary epithelial cell proliferation in intrahepatic bile duct stones.

Objective: Intrahepatic cholangiolithiasis (Intrahepatic bile duct stones, IBDSs) is a common hepatobiliary disease characterized by bile duct obstruction and inflammation, often leading to severe complications such as cholangitis, cirrhosis, and cholangiocarcinoma. This study investigates the role of fat mass and obesity-associated (FTO) protein, an RNA demethylase, in regulating Kupffer cell (KC) polarization, interleukin (IL)-6 secretion, and subsequent human intrahepatic biliary epithelial cell (HiBEC) proliferation in IBDS.

Material and methods: Liver tissues from patients with IBDS were analyzed for FTO expression, KC M2 polarization, and IL-6 levels. In vitro experiments with FTO silencing in KCs were conducted to examine the effects on M2 polarization, IL-6 production, and HiBEC proliferation. Mechanistic analysis focused on the c-Jun N-terminal kinase (JNK)/p38 and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways.

Results: The patients with IBDS showed significantly higher KC M2 polarization, elevated FTO expression, and increased IL-6 levels relative to the controls. Without FTO silencing, IL-6 secretion and HiBEC proliferation remained at high baseline levels. However, FTO silencing reduced M2 polarization, IL-6 secretion, and HiBEC proliferation through the JNK/p38 pathway. Activating the PI3K/AKT pathway partially reversed these inhibitory effects.

Conclusion: FTO plays a critical role in IBDS by promoting the M2 polarization of KCs, which leads to increased IL-6 secretion and induced pathological HiBEC proliferation. Targeting FTO may represent a novel therapeutic strategy for managing IBDS and preventing disease progression.