Hepatocellular carcinoma (HCC) is a malignant tumor with increasing morbidity and mortality worldwide. Despite improvements in treatment and prevention, HCC remains the fourth leading cause of cancer-related deaths [18]. The development of novel therapeutic methods for liver cancer, including adjuvant therapy and immunotherapy, has become a pressing priority in addressing the urgent need to improve the prognosis and treatment of liver cancer patients [19].
Programmed cell death is a crucial process of cellular demise that is regulated by specific genes within the cell [20]. This mechanism plays a vital role in organismal development by eliminating damaged, senescent, or unnecessary cells to regulate cell numbers and maintain a stable intracellular environment. Several programmed cell death pathways have been identified, including the entosis, apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis, cuproptosis, and disulfideptosis pathways [21].
Previous studies have highlighted that in cases of glucose scarcity, tumor cells, in an effort to compete for resources, engage in the engulfment and elimination of similar cells through LC3-related phagocytosis and the cathepsin B-mediated lysosomal degradation pathway. On the other hand, disulfide death is triggered by the abnormal accumulation of disulfide in cells under conditions of glucose scarcity, leading to disulfide stress and subsequent actin cytoskeleton contraction, ultimately resulting in cell death. When glucose resources are scarce, tumor cells compete for resources to trigger entosis, a mode of cell death in which the cell structure of the losing side is dissolved by the winning side. There are many similarities between the two types of cell death. Unfortunately, no prior investigations have elucidated this relationship.
In our study, for the first time, entosis and disulfidptosis were linked to predict the prognosis of liver cancer patients and their tumor immune microenvironment through indirect associations and interactions. This pioneering approach sheds light on the interplay between these two types of cell death, offering valuable insights into their collective impact on liver cancer prognosis and the tumor immune microenvironment.
Our study findings are quite intriguing and provide valuable insights into the molecular mechanisms underlying liver cancer prognosis. By identifying 15 differentially expressed genes (DEGs) from the DRG-ERG region through differential expression analysis and establishing their strong correlation and high expression in liver cancer, we were able to pinpoint their functions related to cell structure, confirming our initial hypothesis. Subsequent Cox regression analysis led to the identification of 8 key genes with high hazard ratios (HRs), which were further refined to 2 prognostic genes, SLC7A11 and KISC2, through LASSO regression analysis. The association of these genes with survival outcomes in the high-risk group versus the low-risk group aligns with our expectations.
The role of SLC7A11 in promoting GSH synthesis and protecting cells from oxidative stress, as well as its potential influence on liver cancer metastasis through the upregulation of PD-L1 and CSF1 [22], underscores its significance in tumor biology [23]. Similarly, the involvement of KIF2C in mitotic chromosome separation and its reported association with tumor prognosis highlight its relevance in cancer research [24]. Investigating the potential interactions between these two genes could provide further insights into their combined impact on liver cancer progression.
Although our study established a promising prognostic model based on the DRG-ERG scoring system, limitations, such as the reliance on public databases and the need for in vitro/in vivo experiments to validate the relationship between different forms of cell death, must be acknowledged. Overall, our research contributes significantly to the understanding of liver cancer prognosis and suggests potential implications for immunotherapy, including the identification of six drugs that may exhibit sensitivity in liver cancer treatment based on the scoring system.