Oxidized LDL reflects inflammatory activity while Lipoprotein(a) tracks fibrotic progression in MASLD

Oxidized low‑density lipoproteins (ox‑LDLs) participate in oxidative stress and inflammation, key players in metabolic dysfunction‑associated steatotic liver disease (MASLD) progression towards steatohepatitis (MASH), fibrosis, cirrhosis and hepatocarcinoma (HCC). Although ox‑LDL has been implicated in cardiometabolic damage, its association with the MASLD spectrum remains unclear. Another lipid-related biomarker, Lipoprotein(a) [Lp(a)], a genetically determined lipoprotein synthesized in the liver, has been previously associated with advanced fibrosis, but its relationship with ox‑LDL and the diagnostic value of their combination is unknown. Aim of this study was to examine the association between ox‑LDL and progressive MASLD, and to determine whether its integration with Lp(a) may improve non‑invasive stratification of disease severity. We evaluated circulating ox‑LDL levels in 587 biopsy‑proven MASLD patients and assessed their association with histological features, metabolic traits, and serum Lp(a). Hepatic ox‑LDL content and expression of scavenger receptors (CD36, LOX‑1) were quantified in liver tissues from a subset of 50 patients. Multivariable regression and ROC analyses were performed to determine the independent and combined predictive value of ox‑LDL and Lp(a). Circulating ox‑LDL was associated with lobular inflammation, ballooning, NAS, and MASH, after adjustment for metabolic risk factors and statin use ( p < 0.05 for all comparisons). No association with fibrosis was observed. Hepatic ox‑LDL levels were higher than circulating concentrations and progressively increased from steatosis to cirrhosis, consistent with the possibility of increased intrahepatic retention and oxidative remodelling in advanced disease. Accordingly, CD36 and LOX‑1 protein levels were increased across disease, especially in cirrhosis (adjusted p < 0.05 vs steatosis). Serum Ox‑LDL and Lp(a) showed a modest inverse correlation and reflected distinct histological MASLD stages. Indeed, at multivariate analysis, ox‑LDL was associated with inflammation whereas low Lp(a) with advanced fibrosis. Unsupervised clustering integrating both biomarkers revealed a high‑risk phenotype (high ox‑LDL + low Lp(a)) with strong discriminative accuracy for MASH with mild-to-moderate fibrosis (F1–F2) (AUC = 0.80). Circulating ox‑LDL levels are associated with the inflammatory stages of MASLD, whereas reduced Lp(a) is associated with fibrotic progression. Their combination delineates a high-risk phenotype characterized by necroinflammatory activity and mild-to-moderate fibrosis, potentially improving MASLD non-invasive stratification.