Hepatic Mechanisms and Therapeutic Target Underpinning Hypercoagulation in Obesity: Insights From Genetic and Transcriptomic Analyses

ABSTRACT Obesity predisposes individuals to hypercoagulation, a key factor in life‐threatening complications like stroke and cardiovascular disease. While clotting factors are primarily secreted by the liver, the mechanisms linking obesity to hypercoagulation remain unclear. In this study, we established an obesity cohort and conducted genetic analyses, single‐nucleus and bulk RNA sequencing of human liver tissues, and in vitro experiments to elucidate the underlying mechanisms. Genetic analysis identified a causal relationship between body mass index (BMI) and coagulation parameters, specifically elevated fibrinogen levels. Clinical cohort data demonstrated a significant association between BMI and plasma fibrinogen levels and fibrinogen function. Hepatic transcriptomic data revealed a significant link between BMI and hepatic fibrinogen expression. snRNA‐seq data and deconvolution analysis of bulk RNA‐seq uncovered a specific hepatocyte subpopulation (Hep5) that was significantly increased and responsible for aberrant coagulation factor secretion in obesity. Pseudotime trajectory analysis indicated that increased interleukin 6 (IL6) signaling in obese patients contributed to the activation of the hepatocyte identity‐related transcription factor CEBPB, promoting the differentiation of other hepatocyte subpopulations into Hep5. Further analysis in an independent obesity cohort confirmed serum IL6 as a critical mediator of the BMI‐fibrinogen relationship, supporting the potential value of IL6 antibodies, which are currently in Phase 2b trials, for improving coagulation abnormalities. In vitro experiments demonstrated that the CEBPB inhibitor helenalin acetate reversed the aberrant expression of hepatocyte differentiation‐related genes induced by IL6. This study defines the hepatic transcriptomic landscape in obesity, elucidates mechanisms of fibrinogen elevation, and highlights therapeutic targets for managing hypercoagulation in obesity.