Integrating bioinformatic analyses and experimental validation of disulfidptosis-related genes and TMX4 in melanoma progression

Melanoma is a highly metastatic and lethal malignancy originating from melanocytes. Disulfidptosis is a recently discovered type of programmed cell death with promising potential in cancer therapy. This study aims to establish a prognostic risk model based on disulfidptosis-related gene signatures and investigate their roles in melanoma progression. Transcriptomic data from the TCGA-SKCM and GEO databases were analyzed to identify disulfidptosis-related gene expression profiles in melanoma. Consensus clustering categorized samples into two molecular subtypes, followed by comprehensive analyses of genomic and immune infiltration characteristics. A prognostic risk model was developed using Lasso regression based on DEGs. The expression and function of TMX4 were further validated using IHC and in vitro experiments, including siRNA-mediated knockdown in A375 and A875 melanoma cell lines. Cell proliferation, migration, and indicators of redox homeostasis (GSH, MDA, and ROS) were evaluated, and SLC7A11 expression was measured to explore underlying mechanisms. Melanoma samples were divided into two subtypes with distinct tumor microenvironments. The eight-gene prognostic model accurately predicted patient outcomes in both training and validation cohorts. TMX4 was highly expressed in melanoma tissues, and its knockdown significantly inhibited the proliferation and migration of melanoma cells. Silencing of TMX4 enhanced oxidative stress by reducing GSH and increasing MDA and ROS, while upregulating SLC7A11 protein expression. The prognosis model based on DRGs has demonstrated potential predictive capability in melanoma. Functional experiments confirmed that TMX4 plays a role in regulating melanoma cell proliferation, migration, and redox homeostasis. These findings suggest that targeting TMX4 and its related pathways (potentially involving disulfidptosis) could be a promising therapeutic strategy for melanoma. However, further studies are required to validate its clinical applicability.