Single-cell and bulk transcriptome analysis unveils a ligand-receptor-based signature for prognostication and reveals that TREM1 controls the malignant behaviors of hepatocellular carcinoma

• • The ligand-receptor-based LASSO model achieved an AUC that, while lower than autophagy- or cuproptosis-focused signatures, provides a broader network view; this trade-off may limit immediate clinical adoption but offers a foundation for multi-pathway integration. • • TREM1 knockdown significantly reduced HCC cell proliferation and migration and increased apoptosis in vitro, with concomitant decreases in IL-1β, TNF-α, and MCP-1, indicating TREM1 as a actionable node for combination immunotherapy. • • In xenograft models, TREM1 downregulation shifted the tumor microenvironment by decreasing M1 macrophages and increasing Tregs, suggesting that TREM1 inhibition could reverse immunosuppression but may require careful timing to avoid compensatory Treg expansion. • • The Nrf2/Keap1 oxidative stress pathway was identified as a key downstream effector of TREM1, with its suppression upon TREM1 knockdown; this links TREM1 to redox homeostasis and presents a potential biomarker for patient stratification in oxidative-stress-targeted trials.