Deciphering the rules of disulfidptosis: a genome-wide signature for identifying disulfidptosis-related genes and analyzing hepatocellular carcinoma chemotherapy sensitivities.

Disulfidptosis, a novel form of regulated cell death (RCD), represents a promising strategy for cancer therapy. However, identifying its regulators remains a key challenge. In this study, we constructed a genome-wide disulfidptosis signature (DS) model using known regulators and large-scale human gene expression data comprising 1454 studies and 272,445 samples. This model predicted disulfidptosis propensity across 33 cancer types and highlighted DS differences across tissues and organs. Functional analysis focused on the top 1 % of high-DS and low-DS genes, revealing their sensitivity to perturbations through simulated overexpression and knockout experiments. In hepatocellular carcinoma (HCC), NRF1 and NRF2 were identified as key disulfidptosis regulators, functioning as a desensitizer and sensitizer, respectively, as validated through gene knockouts, cellular morphology, and functional analyses. Additionally, the ketogenic diet significantly increased cellular sensitivity to disulfidptosis under glucose starvation by promoting metabolic adaptation. Using network pharmacology, small-molecule compounds influencing disulfidptosis were identified. Among these, NR-CL was validated as a disulfidptosis desensitizer, while lomerizine and clioquinol were confirmed as sensitizers through gene expression predictive analyses and cellular functional validation. These findings lay a robust foundation for uncovering novel regulatory mechanisms of disulfidptosis and provide practical strategies for enhancing cancer chemotherapy through targeted interventions.