Tissue-specific profiling of human protein phosphatases identifies G6PC1 as a liver cancer–selective biomarker

Protein phosphatases are essential regulators of cellular signalling, yet their tissue-specific expression profiles and functional roles in cancer remain underexplored. This study aimed to systematically profile protein phosphatases expression across human tissues and malignancies to identify potential biomarkers. The transcriptomic data from GTEx, FANTOM, and HPA, were analysed assessing 265 protein phosphatases across 60 human tissues. Tissue specificity was quantified using the Tau index and coefficient of variation. Top candidates were further evaluated in TCGA and PCAWG cancer cohorts. Protein-level validation was performed using immunohistochemistry (IHC) data from HPA. Functional relevance was investigated through protein-protein interaction (PPI) network analysis and KEGG pathway annotations. G6PC1 emerged as the most liver-specific phosphatase (Tau > 0.99) with high inter-tissue expression variability. Its expression was sharply confined to liver tissue and retained in hepatocellular carcinoma (LIHC), with very low expression across other tumour types. IHC confirmed G6PC1 protein presence in liver cancer samples. PPI analysis positioned G6PC1 as a central metabolic regulator, interacting with key enzymes involved in gluconeogenesis and glucose homeostasis. Notably, G6PC1 expression remained stable across sex, age, tumour stage, ploidy, tumour purity, and tumour mutational burden (TMB) in PCAWG liver cancer patients. This integrative multi-omic analysis identifies G6PC1 as a highly liver-specific, biologically relevant, and potential diagnostic candidate for hepatocellular carcinoma. Its selective expression, protein-level detectability, and network centrality support its potential utility as a diagnostic candidate for liver cancer, warranting further experimental validation in independent clinical cohorts.