Establishment of disulfidptosis-related LncRNA signature as biomarkers in colon adenocarcinoma.

ABSTRACT

PURPOSE: Metabolic reprogramming is a hallmark of cancer and plays a key role in precision oncology treatment. Long non-coding RNAs (lncRNAs) regulate cancer cell behavior, including metabolism. Disulfidptosis, a newly identified form of regulated cell death triggered by glucose starvation, has yet to be fully understood in colon adenocarcinoma (COAD). This study aimed to confirm the existence and role of disulfidptosis in COAD and identify disulfidptosis-related lncRNAs that may be targeted to induce disulfidptosis in COAD. METHODS: PI and F-actin staining were used to observe disulfidptosis in COAD cell lines. Disulfidptosis-related lncRNAs were identified based on the expression of disulfidptosis-associated genes in the TCGA-COAD database. A four-lncRNA signature for disulfidptosis was established. Subsequently, loss-of-function assays explored the roles of AC013652.1 and MCM3AP-AS1 in disulfidptosis. RESULTS: Disulfidptosis was observed in COAD cells under glucose starvation and could be reversed by agents that prevent disulfide stress, such as dithiothreitol (DTT) and tris-(2-carboxyethyl)-phosphine (TCEP). The prognostic value of disulfidptosis-associated genes in COAD patients was confirmed, with higher expression indicating longer survival. A disulfidptosis-related lncRNA signature comprising four lncRNAs was established based on the expression of these genes. Among these, AC013652.1 and MCM3AP-AS1 predicted worse prognoses. Furthermore, inhibiting AC013652.1 or MCM3AP-AS1 increased disulfidptosis-associated gene expression and cellular death, which could be reversed by DTT and TCEP. CONCLUSIONS: This study provides hitherto undocumented evidence of the existence of disulfidptosis and the prognostic value of disulfidptosis-associated genes in COAD. Importantly, we identified lncRNAs AC013652.1 and MCM3AP-AS1, which suppress disulfidptosis and may serve as potential therapeutic targets for COAD.