Endoplasmic reticulum stress related super-enhancers suppress cuproptosis via glycolysis reprogramming in lung adenocarcinoma

Abstract The role of copper in tumor progression is thought to be a double-edged sword. Moderate levels of copper promote tumor progression, while excess copper induces a novel form of programmed cell death known as cuproptosis. However, the relationship between lung adenocarcinoma (LUAD) and cuproptosis remains poorly understood. Copper colorimetric assay identified the progression of LUAD simultaneous associated with higher copper accumulation. Single-cell RNA sequencing further identified the activation of unfolded protein response correlates with copper accumulation, particularly the spliced form of XBP1 (XBP1s). XBP1s negatively regulates the protein level of LIPT1 to inhibit LUAD cell death induced by copper-loaded ionophore elesclomol. CUT&Tag-seq and chromosome conformation capture (3 C) experiment showed that XBP1s affect the frequency of MGRN1 promoter-enhancer interactions in various copper environments by forming super-enhancers. Additionally, MGRN1 promotes the ubiquitination and degradation of LIPT1, which in turn supports glycolysis in LUAD cells. In mouse xenograft models, overexpression of XBP1s significantly inhibits the cuproptosis induced by copper ionophores. Co-administration with SEs inhibitor and copper ionophore also markedly reduced tumor volume and growth rate. Our study sheds light on the molecular mechanism by which XBP1s affect the cuproptosis through super-enhancers formation in LUAD and suggested the potential clinical value of copper ionophore as well as a potential biomarker XBP1s for treatment response.