Dissecting the functions and regulatory mechanisms of disulfidoptosis-related RPN1 in pan-cancer: modulation of immune microenvironment and cellular senescence

Introduction: Cancer's inherent heterogeneity, marked by diverse genetic and molecular alterations, presents significant challenges for developing effective treatments. One such alteration is the regulation of disulfidoptosis, a recently discovered programmed cell death pathway. RPN1, a key regulator associated with disulfidoptosis, may influence various aspects of tumor biology, including immune evasion and cellular senescence. This study aims to dissect the role of RPN1 in pan-cancer and its potential as a therapeutic target.

Methods: We employed a pan-cancer analysis to explore RPN1 expression and its association with clinical outcomes across multiple tumor types. Immune cell infiltration and expression of immune checkpoint genes were analyzed in relation to RPN1. Additionally, cellular senescence markers were assessed in RPN1 knockdown tumor cells. Gene regulatory mechanisms were studied through gene copy number variations, DNA methylation analysis, and transcriptional regulation by SP1.

Results: RPN1 is overexpressed in a wide range of tumor types and correlates with poor clinical outcomes, including overall survival, disease-specific survival, and progression-free intervals. Our analysis shows that RPN1 is involved in immune evasion, correlating with the presence of myeloid dendritic cells, macrophages, and tumor-associated fibroblasts, and influencing T-cell activity. RPN1 knockdown led to reduced tumor cell proliferation and induced cellular senescence, marked by increased senescence-associated biomarkers and β-galactosidase activity. RPN1 expression was found to be regulated by gene copy number variations, reduced DNA methylation, and transcriptional control via SP1.

Discussion: These findings highlight RPN1 as a key pan-cancer regulator, influencing immune microenvironment interactions and cellular senescence. The regulation of disulfidoptosis by RPN1 presents a promising avenue for therapeutic intervention. Targeting RPN1 could enhance immunotherapy efficacy and help mitigate tumor progression, offering a potential strategy for cancer treatment.