Glutaryl-CoA dehydrogenase: a key biomarker linking lysine degradation to hepatocellular carcinoma metastasis and prognosis via NF-KB signaling pathway.

Background: Metastasis is the primary cause of mortality in patients with hepatocellular carcinoma (HCC). Metabolic reprogramming is a well-known hallmark of cancer metastasis. The aim of this study was to elucidate the role of metabolism in HCC metastasis. Methods: Bulk RNA data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases (GEO). A combination of in vitro and in vivo experiments was conducted to evaluate the effects of glutaryl-CoA dehydrogenase (GCDH) on HCC progression. RNA sequencing was performed to investigate the underlying molecular mechanisms. Results: Our findings revealed that lysine degradation pathway activity declined during HCC progression and metastasis. GCDH, a key regulator of the lysine degradation pathway, was selected for further investigation into the role of the lysine degradation pathway in HCC metastasis. The downregulation of GCDH expression promoted HCC metastasis by activating the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, GCDH expression was inversely correlated with macrophage infiltration, suggesting that reduced lysine degradation is associated with modulation of the immunosuppressive microenvironment. This phenomenon was attributed to the upregulation of GDF15 expression, which was induced by decreased GCDH levels through NF-κB signaling. Conclusions: Inhibition of the lysine degradation pathway facilitates HCC metastasis and was involved in immune microenvironment remodeling. Additionally, GCDH may serve as a biomarker for predicting HCC metastasis and prognosis.