Diabetes Mellitus Facilitates Gallstone Formation Through CXCR2‐NETs–Mediated Liver‐Bile Barrier Damage

BACKGROUND: Gallstone disease is a major health burden worldwide, and diabetes is believed to increase the risk of gallstone formation. This study investigates how diabetes promotes gallstone formation and elucidates the underlying mechanism. METHODS: Data from the National Health and Nutrition Examination Survey and Mendelian randomization analyses were used to identify the causal relationship between diabetes and gallstones. Through the integration of multi-omics sequencing and molecular dynamics simulation, CXCR2 was identified as a molecular bridge linking both diseases. Animal models were established, and Western blotting, reverse transcription quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were employed to explore the relevant mechanisms. RESULTS: Clinical data demonstrated that diabetes is an independent risk factor for gallstones. Animal experiments revealed that diabetes upregulated the expression of CXCR2 in hepatic neutrophils, thereby promoting the formation of neutrophil extracellular traps (NETs). Excessive NETs disrupted the tight junctions between hepatocytes, allowing NETs to enter the bile and accelerate gallstone formation. Moreover, sarcosine inhibited CXCR2 expression, reduced NETs production, and decreased gallstone formation. CONCLUSIONS: Diabetes promotes NETs formation through CXCR2 activation, which damages the liver-bile barrier and facilitates gallstone development. Sarcosine may serve as a potential therapeutic agent, providing a theoretical basis for clinical intervention.