Disulfidptosis-related gene expression reflects the prognosis of drug-resistant cancer patients and inhibition of MYH9 reverses sorafenib resistance
Kangnan Zhang, Zhenhua Zhu, Jingyi Zhou, Min Shi, Na Wang, Fudong Yu, Ling Xu
Abstract
• Disulfidptosis-related genes are significantly associated with somatic alteration patterns, immune infiltration, prognosis, and drug sensitivity in various tumors. • Disulfidptosis-related genes are associated with drug sensitivity to various drugs, and MYH9, a disulfidptosis-related gene, plays a vital role in sorafenib resistance in hepatocellular carcinoma. • Inhibiting the expression of MYH9 to a certain extent will increase the expression of SLC7A11. At the same time, it will cause cell shrinkage and F-actin contraction, leading to disulfidptosis-like changes, thereby increasing the drug sensitivity of sorafenib in liver cancer. The onset of drug resistance in advanced cancer patients markedly diminishes their prognosis. Recently, disulfidptosis, a novel form of cell death, has been identified, triggered by excessive disulfide formation leading to cell shrinkage and F-actin contraction. Previous studies have identified 15 essential genes (FLNA, FLNB, MYH9, TLN1, ACTB, MYL6, MYH10, CAPZB, DSTN, IQGAP1, ACTN4, PDLIM1, CD2AP, INF2, SLC7A11) associated with disulfidptosis. This study sourced pan-cancer mRNA expression data from Xena to thoroughly evaluate the molecular and clinical characteristics of disulfidptosis-related genes. Through unsupervised clustering, mRNA expression data identified the expression levels of disulfidptosis-related genes and potential clusters related to this form of cell death. Kaplan-Meier survival curves illustrated the correlation between different clusters and overall survival. The findings reveal that high expression of disulfidptosis-related genes is linked to poor survival in liver cancer. The GDSC database was utilized to analyze the relationship between disulfidptosis-related genes and the AUC of 198 drugs. The results demonstrate that 12 disulfidptosis-related genes influence sorafenib resistance, as revealed by the intersection of differential genes related to sorafenib resistance from the GSE109211 dataset. Among them, the MYH9 gene was found to play a crucial role in both. Finally, experimental evidence confirmed that MYH9 mitigates sorafenib resistance in hepatocellular carcinoma through disulfidptosis-like changes. This study identifies disulfidptosis as a promising avenue for enhancing the sensitivity of tumor cells to drugs, offering new therapeutic perspectives for future research on disulfidptosis and drug resistance in cancer patients. Disulfidptosis is the discovery of a new mode of cell death. There are not many studies on disulfidptosis in tumors. Our study found that there is also a correlation between disulfidptosis-related genes and drug sensitivity. Our experiments showed that inhibiting MYH9 expression in hepatocellular carcinoma attenuates sorafenib resistance. However, previous studies have focused on how MYH9 enhances sorafenib resistance by promoting stemness in hepatocellular carcinoma cells. Our study identified disulfidptosis as a breakthrough that could mitigate sorafenib resistance in cancer by enhancing disulfidptosis-like changes. This has important implications for developing personalized drugs for cancer treatment and overcoming drug resistance.