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

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. This study integrates bioinformatics and functional validation to delineate the interplay between lncRNAs and triaptosis in HCC progression. 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 in malignant hepatocytes. Through systematic bioinformatics analysis of TCGA data, we develop a 5-lncRNA prognostic signature (, , , , ) with superior predictive power over conventional clinical parameters. Strikingly, functional studies reveal that acts as a crucial oncogenic driver and its depletion suppresses proliferation, migration, and invasion while sensitizing cells to triaptosis via -mediated PI(3)P catabolism. Collectively, our study confirms that triaptosis is a therapeutically targetable signaling in HCC and proposes as a biomarker and therapeutic target, offering new insights into lncRNA-mediated regulation of cell death for precision oncology.