Molecular Subtypes Based on Disulfidptosis-related Genes and Tumor Microenvironment Infiltration Characterization in Hepatocellular Carcinoma

Abstract

Abstract The novel discovery of programed cellular death pathway in the field of disulfidptosis has shed light on molecular carcinogenesis and the optimization of anti-tumor therapies. However, the characteristics of disulfidptosis-based molecular classifications and distinct tumor microenvironment-relevant features remain to be disentangled in hepatocellular carcinoma (HCC). In the present study, we comprehensively delineated the molecular landscape of disulfidptosis-related genes (DRGs) and developed DRGs-derived molecular subtypes. Extended investigations of phenotypic linkages between the constructed subtypes and genomic alterations, immune/stromal cell infiltration, immune checkpoints expression, prognostic value and therapeutic agent susceptibility prediction were carried out. Remarkably, our findings demonstrated that DRGs significantly amplified in copy number and upregulated in HCC tumor samples, with enrichment in cancer-promoting processes like MAPK and cAMP signaling pathway. According to DRGs transcriptional profiles, patients with HCC were divided into high- and low-risk groups. To be precise, high-risk group were characterized by higher CTNNB1 mutation frequency and exhausted immune checkpoint expression, together with favorable prognosis. Higher fraction of tumor-associated macrophage and activated memory CD4 + cells were observed in high-risk group, while NK and follicular helper T cells were enriched in low-risk group. Enriched with TP53 mutation and stromal-relevant contents, low-risk group exhibited diminish prognosis, higher immunophenoscore and enhanced sensitivity with 5-fluorouracil, sorafenib and axitinib, indicated that patients in low-risk group probably benefit from combination therapy. In conclusion, our research built up the credible molecular phenotypic linkage between disulfidptosis and hepatic carcinogenesis, unraveling DRGs-based molecular subtypes as trustworthy prognostic indicator and its critical implications in anti-tumor therapy unresponsiveness minimization.