Association between serum methylmalonic acid and metabolic dysfunction-associated steatotic liver disease: NHANES-based study

Methylmalonic acid (MMA) is a marker of mitochondrial dysfunction implicated in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to investigate the association between MMA and MASLD and to evaluate the potential mediating role of the Dietary Inflammatory Index (DII). We analyzed data from 6959 participants in the National Health and Nutrition Examination Survey 1999–2014 using multivariate logistic regression and mediation analysis. After adjusting for covariates, higher MMA levels were associated with a significantly lower risk of MASLD, showing a statistically significant negative dose-response relationship ( P -trend = .048). This inverse association presents a novel perspective, contrasting with the conventional view of MMA as merely a marker of mitochondrial dysfunction. Furthermore, this association was not significantly mediated by DII and appeared to be largely independent of dietary inflammation levels based on stratified and interaction analyses. Importantly, the subgroup analysis revealed that this negative association was more pronounced in males, individuals with normal weight, and those younger than 60 years, demonstrating significant population heterogeneity. MMA shows a significant negative dose-response relationship with MASLD, independent of dietary inflammation. However, this protective association was primarily observed in specific populations, such as males and individuals with normal weight. The mediating effect of DII was not significant. MMA may be a potential protective factor against MASLD. However, these findings should be interpreted with caution due to the cross-sectional study design and the definition of MASLD based on liver enzymes without steatosis assessment.