integrating single-cell transcriptomics and chromatin accessibility profiling to decipher the molecular landscape of Hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent and lethal liver malignancy, characterized by high recurrence rates and limited therapeutic options. Current diagnostic and treatment strategies are hindered by drug resistance and a lack of effective biomarkers for early detection. METHODS: This study aims to elucidate the role of lactylation and fibroblast cells within the tumor microenvironment (TME) of HCC, focusing on their potential as therapeutic targets. Utilizing a comprehensive multi-omics approach, we integrated single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) data from public databases (GEO, TCGA) to explore transcriptional and epigenetic landscapes at single-cell resolution. RESULTS: Our analysis identified fibroblast cells as key players with high lactylation-related pathway activity, and CREB1 as a central transcription factor regulating lactylation-associated genes in these cells. The CREB1 regulatory network was associated with specific immune cell infiltration patterns, drug sensitivity profiles, and enrichment in critical signaling pathways such as Chemokine, TNF, NF-κB, and EMT. These findings underscore the pivotal role of lactylation-driven epigenetic regulation in fibroblasts, influencing the HCC immune microenvironment and disease progression.