From Single-Cell and Bulk Transcriptomic Integration to Functional Verification: Triaptosis-Associated lncRNA Signature Predicts Survival and Guides Therapy in Hepatocellular Carcinoma

<b>Background:</b> Hepatocellular carcinoma (HCC) continues to be a major cause of cancer associated deaths worldwide, highlighting the need for new prognostic biomarkers and treatment strategies. Triaptosis, a recently characterized mode of regulated cell death, has shown potential as a therapeutic target in various malignancies, including HCC. Nevertheless, how long non-coding RNAs (lncRNAs) regulate triaptosis, as well as their function in HCC, is still not well understood. <b>Methods:</b> This study integrates bioinformatics and functional validation to delineate the interplay between lncRNAs and triaptosis in HCC progression. <b>Results:</b> Firstly, we confirm that pharmacologically inducing triaptosis, a process centrally mediated by ROS accumulation, with menadione sodium bisulfite (MSB) can inhibit HCC growth both in vitro and in vivo. Furthermore, single-cell RNA sequencing identifies a specific elevation of the triaptosis-related gene <i>MTM1</i> in malignant hepatocytes. Through systematic bioinformatics analysis of TCGA data, we develop a 5-lncRNA prognostic signature (<i>LINC01134</i>, <i>HPN-AS1</i>, <i>DDX11-AS1</i>, <i>AC009283.1</i>, <i>AC009005.1</i>) with superior predictive power over conventional clinical parameters. Strikingly, functional studies reveal that <i>LINC01134</i> acts as a crucial oncogenic driver and its depletion suppresses proliferation, migration, and invasion while sensitizing cells to triaptosis via <i>MTM1</i>-mediated PI(3)P catabolism. <b>Conclusions:</b> Collectively, our study confirms that triaptosis is a therapeutically targetable signaling in HCC and proposes <i>LINC01134</i> as a biomarker and therapeutic target, offering new insights into lncRNA-mediated regulation of cell death for precision oncology.