Dynamic Alterations of BMP9 in NAFLD: A Novel Hepatokine Marker of Metabolic Dysfunction and Disease Severity

Purpose: Bone morphogenetic protein 9 (BMP9), a hepatokine belonging to the transforming growth factor-β (TGF-β) superfamily, plays a critical role in glucose and lipid metabolism. This study aimed to investigate the dynamic changes of BMP9 under metabolic stress in patients with different severities of non-alcoholic fatty liver disease (NAFLD), and to evaluate its associations with metabolic abnormalities and clinical diagnostic value. Patients and Methods: A total of 84 participants were enrolled and categorized into normal control (Con), mild, moderate, and severe NAFLD groups. Standardized oral fat tolerance tests (OFTT) were conducted to assess dynamic alterations in circulating BMP9 and related metabolic indices. Trend analysis, Spearman correlation, multivariate regression, and receiver operating characteristic (ROC) curve analyses were performed to explore the relationships between BMP9 and metabolic parameters as well as its diagnostic performance. Results: Both fasting and postprandial BMP9 levels declined with increasing NAFLD severity, with a more pronounced reduction observed in the severe group (P < 0.05). In the severe NAFLD group, baseline BMP9 levels were reduced by 47.2%, and the time-integrated area under the concentration–time curve (AUC) was reduced by 52.7% compared with controls. The BMP9 AUC was negatively correlated with BMI, HOMA-IR, TG, and LDL-C, and positively correlated with HDL-C (all P < 0.05). Multivariate regression identified HOMA-IR and TG as independent predictors of lower BMP9 levels. Furthermore, ROC analysis demonstrated excellent diagnostic performance of BMP9 AUC in identifying moderate-to-severe NAFLD (ROC-AUC = 0.965). Conclusion: BMP9 exhibits both basal deficiency and functional impairment in NAFLD and is closely associated with multiple metabolic abnormalities. Its dynamic profile may represent a promising early diagnostic biomarker for NAFLD and could potentially serve as a tool for metabolic disease screening and intervention. Plain Language Summary: Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a common condition linked to obesity, diabetes, and heart disease. Finding simple blood markers to detect the disease early is important. In this study, we measured the blood levels of bone morphogenetic protein 9 (BMP9), a hormone produced by the liver, in people with NAFLD. We found that BMP9 levels were significantly lower in patients compared with healthy individuals, and the decrease was related to the severity of liver fat and metabolic problems. After a standardized meal test, BMP9 levels changed in a dynamic way that reflected the body’s metabolic response. These findings suggest that BMP9 may serve as a promising biomarker for early detection and monitoring of NAFLD/MASLD. Keywords: hepatic steatosis, postprandial metabolism, lipid homeostasis, dysglycemia, insulin resistance, bone morphogenetic protein 9