Abstract
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health burden globally, associated with multiple adverse outcomes and increased mortality. Sedentary behavior and systemic inflammation are independently linked to adverse outcomes, but their combined effects and potential interactions in the MASLD population remain unclear. METHODS: We used data from 10,778 U.S. adults with MASLD from NHANES 2007-2018. MASLD was identified using the Fatty Liver Index (FLI ≥ 60), a validated and widely applied noninvasive indicator of hepatic steatosis in NHANES-based epidemiologic studies, providing a reliable estimate of liver fat probability for population analyses. Sedentary time was assessed by questionnaire. The systemic inflammation response index (SIRI) was determined to be the most effective inflammatory marker among the 12 inflammatory indicators using time-dependent receiver operating characteristic curves. Weighted Cox proportional hazards models were used to evaluate associations with all-cause, cardiovascular disease (CVD), and cancer mortality. Restricted cubic spline (RCS) analysis was performed to assess nonlinear relationships. Joint associations and mediation analysis were conducted to explore joint effect and the mediating role of SIRI in the sedentary time-mortality relationship. RESULTS: A total of 1028 deaths occurred over the follow-up duration (median: 78 months), comprising 340 cardiovascular and 256 cancer-related. Longer sedentary time and elevated SIRI were independently associated with increased all-cause and CVD mortality. Compared with participants with low sedentary time and low SIRI, those with both high sedentary time (≥ 3.81 h/day) and high SIRI (≥ 0.81) had a 62% higher risk of all-cause mortality (HR 1.62, 95% CI 1.14-2.31) and a 137% higher risk of CVD mortality (HR 2.37, 95% CI 1.45-3.86). Mediation analysis showed that SIRI statistically explained 16.5% of the association between sedentary time and all-cause mortality and 14.7% of the association with CVD mortality. CONCLUSIONS: In U.S. adults with a high probability of MASLD identified by the FLI, both longer sedentary time and elevated systemic inflammation level are linked to increased risks of all-cause and CVD mortality. Moreover, inflammation statistically explains part of this association. These findings highlight the importance of reducing sedentary time and managing systemic inflammation to improve outcomes in individuals with FLI-defined MASLD.