ASPDH inhibits the proliferation, migration, and invasion of liver cancer cells by regulating lactate metabolism and the NF-κB/PD-L1 pathway.

backgroundLactate has been proven to be an important metabolite involved in tumor initiation, progression, and tumor microenvironment, affecting patient prognosis. The role of lactate metabolism-related genes in liver cancer is unclear.

methodsThe authors identified lactate metabolism-related genes from five key pathways and scored their relevance. Genetic and clinical data from TCGA-LIHC and validation cohorts (GSE54236, ICGC, and GSE116174) were analyzed to confirm survival associations. Sodium lactate rescue experiments were performed on ASPDH-overexpressing cells to investigate the role of lactate. In vivo xenograft models verified ASPDH's effects on tumor growth and NF-κB/PD-L1 signaling.

resultsFrom 320 lactate metabolism-related genes, four core genes were identified: LPCAT1, TMEM220-AS1, ASPDH, and LECT2. Low ASPDH expression correlated with poorer survival across multiple datasets. PD-L1 ROC analysis showed high diagnostic efficacy (AUC = 0.8). ASPDH knockdown enhanced proliferation, colony formation, migration, and invasion, while overexpression had opposite effects. Sodium lactate rescue experiments further demonstrated that exogenous lactate partially restored cell proliferation, migration, and invasion abilities suppressed by ASPDH overexpression, along with increased nuclear p65 and PD-L1 expression, confirming lactate's role in mediating ASPDH-regulated NF-κB pathway activity and PD-L1 expression. GSEA linked ASPDH to PD-L1 expression and checkpoint pathways. In vivo, ASPDH overexpression suppressed tumor growth, decreased nuclear p65 and PD-L1, and increased cytoplasmic p65, alongside reduced lactate secretion and NF-κB/PD-L1 modulation.

conclusionASPDH inhibits liver cancer cell proliferation, migration, and invasion by downregulating lactate secretion and suppressing the NF-κB/PD-L1 signaling pathway.