Gcdh, or glutaryl-CoA dehydrogenase, is a mitochondrial protein crucial for lysine metabolism. It functions in converting glutaryl-CoA to crotonyl-CoA, thereby controlling protein glutarylation [1,2,3]. This process is integral to lysine catabolism and impacts multiple biological processes. Genetic models, such as knockout mouse models, have been instrumental in studying Gcdh's functions.

In melanoma cells, Gcdh knockdown induced cell death, which was blocked by inhibiting the upstream lysine catabolism enzyme DHTKD1. Mechanistically, Gcdh knockdown led to NRF2 glutarylation, increasing its stability and DNA binding activity, and upregulating genes like ATF4, ATF3, DDIT3, and CHAC1 [1].

In glioblastoma stem cells, upregulation of Gcdh along with SLC7A2 and downregulation of ECHS1 reprogrammed lysine catabolism, leading to intracellular crotonyl-CoA accumulation and histone H4 lysine crotonylation [2].

In hepatocellular carcinoma, Gcdh depletion promoted tumor growth and metastasis, while overexpression reversed these processes. Gcdh-induced crotonylation of PPP and glycolysis-related proteins limited the Warburg effect and induced senescence, shaping an anti-tumor immune microenvironment [3].

In conclusion, Gcdh is essential for lysine metabolism and protein glutarylation. Model-based research, especially Gcdh knockout mouse models, has revealed its role in diseases such as melanoma, glioblastoma, and hepatocellular carcinoma. These findings provide potential therapeutic targets for treating these malignancies.