Aberrant Cholesterol Metabolism Caused by Decreased Lecithin: Cholesterol Acyltransferase Promoted...

Hepatocellular carcinoma (HCC), the most common primary liver cancer, exhibits metabolic reprogramming with disrupted cholesterol metabolism as a key feature. Lecithin-cholesterol acyltransferase (LCAT) contributes to HCC development, but its exact on cogenic mechanisms remain unclear. This study aims to investigate the role of LCAT in hepatocarcinogenesis and elucidate its underlying molecular mechanisms in HCC.

The Cancer Genome Atlas (TCGA), GEPIA, and Kaplan-Meier plotter databases were used to analyze LCAT expression and perform survival analysis and functional enrichment analysis. Clinical paired samples were collected to evaluate LCAT expression and observed changes in cholesterol metabolism levels Liver-specific Lcat knockout mice were constructed to investigate the hepatocarcinogenesis effect of LCAT. Loss-of-function studies were performed to confirm the molecular mechanism of LCAT in HCC. Finally, investigated the correlation between LCAT and immune infiltration.

LCAT expression level was down-regulated in HCC patients and low LCAT level was associated with poor prognosis. International Cancer Genome Consortium (ICGC) data reveal dysregulated cholesterol metabolism in HCC, further validated by clinical evidence of metabolic aberrations in patients Besides, we constructed DEN induced HCC model using Alb-Cre; Lcat^fl/fl mice and found that liver-specific Lcat knockout promoted cancerogenesis through ERK pathway. Meanwhile, knockdown of LCAT significantly promoted proliferation, migration, and invasion in Huh7 cell. Finally, immune infiltration analysis showed that LCAT was significantly related to immune infiltration, and LCAT expression was significantly associated with more than 10 immune checkpoint markers such as IL12A, VTCN1, BTLA, and TIGIT.

This study first explored the biological functions of LCAT in HCC based on in vitro and in vivo experiments. Our results indicate that LCAT deficiency correlates with aggressive HCC progression and immunosuppression, suggesting its potential as a prognostic biomarker. Given its role in modulating the HCC microenvironment, LCAT warrants further investigation as a predictive marker for immunotherapy response.