Association of the C-reactive protein-triglyceride glucose index with all-cause and cardiovascular mortality among U.S. adults with metabolic dysfunction-associated steatotic liver disease: a national cohort study

Background: Insulin resistance and systemic inflammation are recognized as primary contributors to the development of metabolic dysfunction–associated steatotic liver disease (MASLD). Nevertheless, the relationship between the C-reactive protein-triglyceride glucose index (CTI), a novel composite marker reflecting both systemic inflammation and insulin resistance, and mortality in MASLD patients has not yet been clearly established. Methods: Data from 5,029 MASLD patients enrolled in the National Health and Nutrition Examination Survey (1999–2010, 2015–2018) were analyzed. Participants were categorized into CTI quartiles. Associations between CTI, all-cause mortality (ACM), and cardiovascular mortality (CVM) were assessed through multivariate Cox proportional hazards models and restricted cubic spline analyses to evaluate both linear and nonlinear relationships. Mediation and subgroup analyses were conducted to identify factors that mediate or modify the CTI–mortality association. Additional sensitivity analyses were conducted to evaluate the stability and reliability of the findings. Results: Over a median follow-up of 122 months, a total of 1,072 ACMs and 352 CVMs were observed. Participants in the highest CTI quartile had a significantly elevated risk of ACM (HR: 1.86; 95% CI: 1.50–2.31; P < 0.001) and CVM (HR: 2.07; 95% CI: 1.44–2.97; P < 0.001) compared to those in the lowest quartile. Restricted cubic spline analysis revealed a significant nonlinear relationship, with mortality risk rising sharply for CTI values above 8.8. Subgroup analyses revealed significant interactions with age and the fibrosis-4 index, with stronger associations observed in participants younger than 60 years and those with lower fibrosis-4 scores. Exploratory mediation analysis identified several metabolic and inflammatory markers as potential mediators, including neutrophils (mediation proportion: 16%) and glycated hemoglobin (mediation proportion: 33%) for the CTI-ACM link. Adding CTI to a conventional risk model provided the greatest improvement in discriminatory ability for both ACM and CVM compared to CRP or TyG index alone. Sensitivity analyses supported the robustness of the results. Conclusion: Elevated CTI values are significantly associated with increased ACM and CVM among MASLD patients. CTI may serve as a unique marker for risk stratification within this group. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at 10.1186/s12933-026-03163-7.