Distinct Plasma Proteomic Signatures Distinguish MASLD From Non‐Steatotic Individuals but Not From MetALD

ABSTRACT Background and Aims Metabolic dysfunction associated steatotic liver disease (MASLD) is the most prevalent liver disease, yet accurate early detection remains challenging. A particular diagnostic obstacle is distinguishing MASLD from metabolic dysfunction and alcohol‐related liver disease (MetALD), currently defined using clinically informed moderate alcohol consumption thresholds without biological validation. This study aimed to identify and externally validate plasma proteomic signatures associated with MASLD and assess whether proteomic profiles support a molecular distinction between MASLD and MetALD as currently defined. Methods We analysed plasma proteomic profiles using OLINK data from UK Biobank (UKB) participants with liver MRI. MASLD was defined as MRI‐PDFF ≥ 5% and metabolic dysfunction ( n = 165), MetALD ( n = 46) as MASLD with additional moderate alcohol intake and controls as PDFF < 5% ( n = 741). Results Compared to controls, participants with MASLD showed 17 upregulated and 3 downregulated proteins after Bonferroni correction (adjusted p < 0.05). Among upregulated proteins, leptin (LEP), fatty acid‐binding protein, liver (FABP1) and aminoacylase1 (ACY1) and among downregulated, insulin‐like growth factor‐binding protein 1 (IGFBP1) were externally validated in an independent cohort (clinicaltrials.gov NCT02520609, n = 47). Individuals with MetALD showed no significant proteomic distinction from MASLD. Although the small MetALD sample size may have limited detection of differences, direct differential expression analysis did not identify statistically significant differences between MASLD and MetALD under the current clinical thresholds. Conclusions MASLD was associated with a reproducible plasma proteomic signature enriched for proteins involved in lipid metabolism, inflammation and hormonal regulation. We did not identify a clear proteomic distinction between MASLD and MetALD under the current alcohol thresholds. However, this finding should be interpreted considering limited power and potential alcohol‐exposure misclassification.