Disulfidptosis and pentose phosphate pathway-associated prognosis signature guides immunotherapy for lung adenocarcinoma patients

Background Disulfidptosis is a form of cell death, where generation of nicotinamide adenine dinucleotide phosphate (NADPH) through the pentose phosphate pathway (PPP) play an important role. The discovery of disulfidptosis provides new in-sights into lung adenocarcinoma (LUAD) therapeutics. Research Design and Methods: Disulfidptosis regulators (DSRs) was used to identify subgroups. Meanwhile, WGCNA and single-cell analysis were performed to identify genes related to disulfidptosis and PPP (DPRGs). To determine the risk signature, clinical features were analyzed, as well as prognostic pre-dictive ability, tumor immune microenvironment (TIME), immunotherapeutic response and drug sensitivity. Finally, the results were experimentally verified in vitro and vivo. Results We identified two DSR and DPRG clusters associated with distinct immune profiles involved in regulating different biological processes. The risk signature was effective in assessing LUAD prognosis in patients. It showed a strong correlation with TIME and could predict the immunotherapy response. After LRRC61 knockdown, the proliferation, migration and anti-apoptotic ability of LUAD cells were significantly reduced. Moreover, the xenograft tumors showed tumour growth was promoted when overexpressing LRRC61. Conclusion We analyzed DSRs and DPRGs in LUAD and developed an evaluation system that assesses the risk and guides the clinical application of drugs, including chemotherapeutic and immunotherapeutic agents.