Integrating bulk RNA-seq, scRNA-seq, and spatial transcriptomics data to identify novel post-translational modification-related molecular subtypes and therapeutic responses in hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) poses considerable difficulties regarding the prognosis and the assessment of treatment efficacy. Additionally, while it is recognized that post-translational modification (PTM) plays a crucial role in modulating HCC progression, their specific prognostic implications in HCC have not been thoroughly investigated. METHODS: 21 types of PTM (acetylation, succinylation, malonylation, crotonylation, β-hydroxybutyrylation, lactylation, palmitoylation, myristoylation, SUMOylation, NEDDylation, ISGylation, ATG8ylation, FAT10ylation, UFMylation, methylation, glycosylation, biotinylation, S-nitrosylation, phosphorylation, ubiquitination, deubiquitination) were generated consensus cluster. Then, WGCNA was utilized to identify module genes. Finally, a machine learning approach was employed to create PTM.score. RESULTS: This analysis revealed two distinct subtypes of PTMs, each characterized by unique molecular signatures. By integrating different categories of genes, including prognosis-related DEGs, module genes, and PTM-related genes, 15 hub genes were identified, and a PTM.score was developed. PTM.score was rigorously validated across independent external cohorts (TCGA-LIHC, LIRI-JP, GSE10143, GSE14520, GSE27150, GSE36376, and GSE76427) and an in-house cohort, demonstrating its reliability and potential applicability. In addition, patients categorized with a low PTM.score displayed a TME that was more actively engaged, which corresponded with a poor prognosis. Furthermore, these patients demonstrated a high level of responsiveness to immunotherapy interventions. Furthermore, an examination using scRNA-seq and spatial transcriptomics indicated that patients with low PTM.score exhibited heightened cell proliferation and malignancy. CONCLUSION: This novel PTM-related prognostic signature could effectively assess the prognosis and therapeutic responses of HCC patients, providing new perspectives for individualized treatment for the patient population.