Long non-coding RNAs (lncRNAs) exert substantial influence on the development and metastatic spread of gastric cancer (GC). Despite this, systematic studies using tissue-derived lncRNAs to predict peritoneal recurrence in GC patients remain insufficient. The current investigation aims to delineate the lncRNA transcriptional profile in GC with peritoneal metastasis (PM) and to develop an integrated lncRNA-derived scoring system to predict peritoneal recurrence in individuals undergoing radical gastrectomy. Transcriptomic analysis of lncRNAs was conducted on matched samples of peritoneal tissue, primary gastric tumors, and adjacent normal tissues collected from 12 GC patients within the Sun Yat-sen University Cancer Center (SYSUCC) discovery set. Candidate lncRNAs were pinpointed by cross-referencing findings with the TCGA database and an independent SYSUCC validation cohort. A prognostic risk model was generated through LASSO regression, followed by construction of a nomogram based on Cox proportional hazards regression. The model’s discriminatory performance was evaluated using receiver operating characteristic (ROC) curve analysis. The functional effects of lncRNAs on PM were subsequently validated using wound-healing assays, Transwell migration/invasion assays, three-dimensional multicellular tumor spheroid invasion models, and in vivo peritoneal xenograft experiments in mice. Five pivotal lncRNAs were identified and assembled into a PM risk score designed to estimate peritoneal recurrence-free survival (pRFS). An integrated nomogram combining this PM risk score with pT stage, pN stage, and tumor size was established, achieving robust prediction of 5-year pRFS with an area under the curve of 0.79 (95% CI: 0.71-0.88). Functional experiments further showed that CASC15, one of the selected lncRNAs, significantly augmented the migratory and invasive abilities of GC cells in vitro and accelerated peritoneal dissemination in vivo. These findings provide direct evidence of lncRNA involvement in GC peritoneal metastasis. Mechanistic studies revealed that CASC15 drives epithelial-mesenchymal transition and metastatic behavior by activating the JNK and p38 signaling cascades. The present study developed an integrated lncRNA-based scoring tool to predict peritoneal recurrence in GC patients.
