ABSTRACT
BACKGROUND:
Hepatocellular carcinoma (HCC) is a highly prevalent and deadly
cancer, with limited
treatment options for advanced-stage
patients. Disulfidptosis is a recently identified mechanism of
programmed cell death that occurs in SLC7A11 high-expressing
cells due to
glucose starvation-induced disintegration of the cellular
disulfide skeleton. We aimed to explore the potential of disulfidptosis, as a prognostic and
therapeutic marker in HCC.
METHODS:
We classified HCC
patients into two disulfidptosis subtypes (C1 and C2) based on the transcriptional profiles of 31 disulfrgs using a non-negative matrix factorization (NMF)
algorithm. Further, five
genes (NEIL3, MMP1, STC2, ADH4 and CFHR3) were screened by Cox
regression analysis and
machine learning algorithm to construct a disulfidptosis scoring system (disulfS).
Cell proliferation assay,
F-actin staining and PBMC
co-culture model were used to validate that disulfidptosis occurs in HCC and correlates with
immunotherapy response.
RESULTS:
Our results suggests that the low disulfidptosis subtype (C2) demonstrated better overall
survival (OS) and
progression-free survival (PFS)
prognosis, along with lower levels of immunosuppressive
cell infiltration and activation of the
glycine/
serine/
threonine metabolic pathway. Additionally, the low disulfidptosis group showed better responses to
immunotherapy and potential antagonism with
sorafenib treatment. As a total
survival risk factor, disulfS demonstrated high predictive
efficacy in multiple validation cohorts. We demonstrated the presence of disulfidptosis in HCC
cells and its possible relevance to immunotherapeutic sensitization.
CONCLUSION:
The present study indicates that novel
biomarkers related to disulfidptosis may serve as useful clinical diagnostic
indicators for
liver cancer, enabling the prediction of
prognosis and identification of potential
treatment targets.