Integrated WGCNA and Experimental Validation Reveals LINC00595 as Necroptosis-Regulating lncRNAs in Prostate CancerOA

Objectives:Prostate cancer(PCa)is a highly prevalent male malignancy with limited efficacy in advanced stages.Dysregulated modulation of necroptosis was reported to be tightly correlated with PCa initiation and progression.Herein,we aimed to identify necroptosis-associated long non-coding RNAs(lncRNAs)and delineate their functional roles in PCa through an integrated approach combining bioinformatic analyses and in vitro experimental validation.Methods:RNA sequencing data and corresponding clinical information of PCa were downloaded from The Cancer Genome Atlas(TCGA).Differentially expressed necroptosis-related genes(NRGs)and lncRNAs were screened,and necroptosis activity was assessed by single-sample gene set enrichment analysis(ssGSEA).Weighted Gene Co-expression Network Analysis(WGCNA)identified necroptosis-related lncRNA modules,with key lncRNAs prioritized via Cox regression.Clinical correlation analyses and in vitro experiments validated the function of the key lncRNA LINC00595.Results:A total of 50 differentially expressed NRGs were identified,among which pro-necroptotic genes exhibited pronounced downregulation,while anti-necroptotic genes were significantly upregulated.Consistently,ssGSEA confirmed reduced necroptosis activity in PCa.WGCNA further identified 13 core necroptosis-related lncRNAs(NRlncRNAs),with Cox regression analysis pinpointing LINC00595 and LINC00908 as the top prognostic candidates.Both lncRNAs were downregulated in PCa,with low expression correlating with advanced T stage,lymph node metastasis,and poor prognosis.Functional experiments demonstrated that LINC00595 overexpression inhibited PCa cell proliferation,migration,and invasion,and enhanced necroptosis.Conclusions:Collectively,our findings identified LINC00595 and LINC00908 as novel regulators of necroptosis in PCa.Specifically,LINC00595 exerted tumor-suppressive effects by enhancing necroptosis,holding potential as prognostic biomarkers and therapeutic targets.