Background <p>Liver fibrosis is the strongest predictor of long-term clinical outcomes in patients with metabolic dysfunction-associated steatotic liver disease MASLD. Non-invasive methods for identifying these patients are urgently needed. We aimed to investigate the link between the transforming growth factor-β induced protein Ig-H3 (BIGH3) and fibrosis in both diet-induced mouse model and patients with MASLD, and explore its potential use as a biomarker for MASLD related fibrosis.</p> Methods <p>Hepatic gene expression and serum BIGH3 levels were studied in two diet -induced MASLD models. Forty patients with biopsy-proven MASLD were recruited. Serum BIGH3 levels were measured by enzyme-linked immunosorbent assays. The difference between groups with or without fibrosis was analyzed using the Mann–Whitney U test. BIGH3 levels across different fibrosis stages were analyzed using Spearman correlation, Kruskal–Wallis test, and Dunn’s post-hoc test. The receiver operating characteristic (ROC) curve was used to explore its value in the diagnosis of MASLD related fibrosis.</p> Results <p><i>Bigh3</i> was identified as a fibrosis-related gene in the liver. Serum BIGH3 levels were significantly higher in the mouse model of fibrosis than in controls (<i>P</i> &lt; 0.01). Additionally, serum BIGH3 levels were significantly elevated in MASLD patients with fibrosis compared to those without fibrosis (<i>P</i> &lt; 0.01), and showed a stepwise increase corresponding to the degree of fibrosis (<i>ρ</i> = 0.55, <i>P</i> &lt; 0.01). The areas under the receiver operating characteristic curve to discriminate significant fibrosis were 0.790 (<i>P</i> &lt; 0.01).</p> Conclusion <p>BIGH3 is a potential non-invasive biomarker of MASLD related fibrosis. It may be beneficial for diagnosing significant fibrosis in MASLD patients.</p>