Elevated serum neprilysin levels in patients with chronic hepatitis C and metabolic dysfunction-associated steatotic liver disease: hepatic oxidative stress as an underlying mechanism

Background Neprilysin (NEP) is a metalloprotease that has become a therapeutic target for the treatment of heart failure and hypertension. However, the significance of NEP in chronic liver diseases has rarely been investigated. In this study, we investigated the serum NEP levels in patients with chronic liver disease and their relationship with clinical parameters. Methods and results Thirty-seven patients with chronic hepatitis C (CHC) who achieved sustained virologic response (SVR) after antiviral treatment and 73 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled. Serum neprilysin levels were measured using an enzyme-linked immunosorbent assay. The median NEP levels were 2.2 ng/mL in CHC and 4.1 ng/mL in MASLD, with the latter being significantly higher. Notably, in patients with MASLD, a significant correlation was observed between NEP and gamma-glutamyltransferase (GGT) levels at baseline. In contrast, there was no significant correlation between NEP levels and progression of liver fibrosis in either group. In the MASLD group, obesity and lifestyle diseases were significantly more prevalent, and the patients exhibited significantly higher NEP levels. In patients with CHC, NEP levels significantly decreased after SVR. NEP mRNA expression in liver tissues was significantly downregulated following SVR. Furthermore, a significant correlation was observed between the degree of NEP and GGT improvement. Conclusions Elevated NEP levels were observed in both CHC and MASLD groups. Considering the association between NEP levels and obesity, lifestyle diseases, and GGT levels, this suggests that oxidative stress may be involved in the elevation of NEP levels in patients with CHC and MASLD.