Citrullinated matrisome: An emerging stromal determinant in hepatocellular carcinoma prognostication

Accurate prognostic stratification of hepatocellular carcinoma (HCC) remains a significant clinical challenge. Although the TNM staging system and serum alpha-fetoprotein levels provide a foundational framework for risk assessment, there is an urgent need for biomarkers that reflect the intrinsic biological aggressiveness of both the tumor and its microenvironment. In this editorial, we discuss the pivotal study by Cho et al , which identifies elevated expression of citrullinated glial fibrillary acidic protein (cit-GFAP) as a novel and independent prognostic marker associated with reduced overall survival (OS) following curative hepatic resection. We situate these findings within the broader context of HCC biology, highlighting the critical contributions of the tumor microenvironment and post-translational modifications. The study successfully bridges stromal biology with protein citrullination, demonstrating that high cit-GFAP expression is significantly correlated with increased mortality, independent of conventional prognostic factors such as tumor size. We examine the biological plausibility of this association, considering the role of glial fibrillary acidic protein in hepatic stellate cell activation and the growing body of evidence linking citrullination to extracellular matrix remodeling and cancer progression. Additionally, we offer a critical evaluation of the study’s implications, acknowledge its limitations—particularly its retrospective design and the observed discrepancy between OS and recurrence-free survival—and propose a forward-looking research agenda focused on biomarker validation and translational development. The identification of cit-GFAP underscores the matrisome as a promising reservoir of prognostic biomarkers and potential therapeutic targets, thereby advancing the mechanistic understanding of HCC pathogenesis.