Plasma proteome profiling identifies XPNPEP3 as a novel biomarker associated with metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus

To identify plasma protein differences between type 2 diabetes mellitus (T2DM) patients with and without metabolic dysfunction-associated steatotic liver disease (MASLD), and to evaluate the diagnostic potential of X-prolyl aminopeptidase 3 (XPNPEP3) for identifying MASLD in T2DM patients.
Twenty T2DM inpatients were categorized into groups with and without MASLD and their plasma samples were analyzed using data-independent acquisition mass spectrometry, followed by bioinformatics analysis to identify differentially expressed proteins. The cohort was then expanded to 84 patients, and plasma XPNPEP3 levels were validated by enzyme-linked immunosorbent assay. Correlation between XPNPEP3 and clinical indicators were evaluated, and diagnostic performance was determined via receiver operating characteristic (ROC) analysis. Immunohistochemistry was employed to compare hepatic XPNPEP3 expression between the two groups.
Proteomic analysis identified 176 differentially expressed proteins, with XPNPEP3 exhibiting the most significant down-regulation by fold change. In the validation cohort, plasma XPNPEP3 was significantly lower in T2DM+MASLD versus T2DM alone. XPNPEP3 levels were negatively correlated with diabetes duration, liver function markers, and triglyceride levels, and was identified as an independent factor inversely associated with MASLD in T2DM.ROC analysis demonstrated strong diagnostic performance for XPNPEP3, further enhanced when combined with BMI and diabetes duration.  Immunohistochemistry confirmed reduced hepatic XPNPEP3 expression in T2DM+MASLD patients.
Lower plasma XPNPEP3 is independently associated with MASLD in T2DM patients and demonstrates strong diagnostic potential, positioning XPNPEP3 as a promising biomarker for diagnosing MASLD in T2DM patients and a novel target for non-invasive diagnostic tool development.

Plasma proteomic profiling identifies XPNPEP3 as a novel and significantly downregulated biomarker in patients with T2DM and comorbid MASLD.
Plasma XPNPEP3 levels are independently and inversely associated with MASLD in T2DM and show good discriminatory ability, particularly when combined with clinical indicators such as BMI and diabetes duration.
The downregulation of XPNPEP3, confirmed at the target organ level in liver tissue, underscores its role in the pathophysiology linking T2DM and MASLD.

Plasma proteomic profiling identifies XPNPEP3 as a novel and significantly downregulated biomarker in patients with T2DM and comorbid MASLD.
Plasma XPNPEP3 levels are independently and inversely associated with MASLD in T2DM and show good discriminatory ability, particularly when combined with clinical indicators such as BMI and diabetes duration.
The downregulation of XPNPEP3, confirmed at the target organ level in liver tissue, underscores its role in the pathophysiology linking T2DM and MASLD.