Life's crucial 9, plasma proteomics, and the risk of major complications and mortality in MASLD

Metabolically dysfunction-associated steatotic liver disease (MASLD) constitutes a major health burden. Whether a multidomain profile of modifiable health, as captured by Life's Crucial 9 (LC9), is associated with major complications in MASLD, and which plasma proteins underlie these associations, remains unclear. We evaluated LC9 in 59,433 individuals with MASLD, including 6,354 with plasma proteomic data. During a median follow-up of 13.8 years, participants in the highest versus lowest LC9 tertile had lower risks of major adverse cardiovascular events (HR 0.62), major adverse liver outcomes (HR 0.62), chronic kidney disease (HR 0.54), chronic respiratory disease (HR 0.63), all-cause mortality (HR 0.67), and cardiovascular mortality (HR 0.55). LC9 modestly improved discrimination for incident complications, but not materially for mortality. Proteomic analyses identified candidate mediators shared across outcomes, including FABP4 and HAVCR1. Our findings suggest LC9 provides a multidomain framework for MASLD risk stratification, offering candidate protein signatures for future mechanistic evaluation.