C-peptide in MASLD – a potential driver of hepatic steatosis and fibrosis

Abstract Metabolically-dysfunction-associated steatotic liver disease (MASLD), the leading chronic liver condition worldwide, is driven by hyperinsulinemia and insulin resistance, with C-peptide serving as a stable marker of endogenous insulin secretion. In this perspective, we propose to redefine C-peptide as an active driver rather than a passive marker in MASLD pathogenesis. In our July 2025 cross-sectional study of 118 participants, we demonstrated that elevated serum C-peptide independently signals fibrosis risk in obese patients with MASLD, showing moderate correlation with the non-alcoholic fatty liver disease (NAFLD) Fibrosis Score, acceptable discriminatory performance (AUC 0.75 at cut-off 1.78 ng/mL), and a linear relationship in regression modelling. Subsequent studies from late 2025 to early 2026 have advanced this foundation. Refined indices, such as the fasting C-peptide/HDL-C ratio (FHR) and HOMA2 IR-CP, exhibit nonlinear associations and superior predictive accuracy for MASLD in type 2 diabetes. Recently, C-peptide has been identified as a primary causal driver of hepatic steatosis, independent of peripheral resistance. We propose that C-peptide has evolved from a fibrosis biomarker to a mechanistic node and actionable target. Routine integration into metabolic screening could enhance early risk stratification and monitoring of therapies modulating hyperinsulinemia. The relatively small sample size of our cross-sectional cohort need more studies on larger scale. C-peptide deserves further study as a possible biomarker in future prospective trials validating its role in MASLD pathophysiology.