Gart, or glycinamide ribonucleotide transformylase, is a trifunctional polypeptide with phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, and phosphoribosylaminoimidazole synthetase activity. It is essential for de novo purine biosynthesis and is highly conserved in vertebrates [3]. Gart is involved in multiple signaling pathways, such as the Wnt/β -catenin pathway, and plays a significant role in various biological processes and disease conditions.

In colorectal cancer, Gart has a novel methyltransferase function. Its enzymatic activity center is at the E948 site, and it enhances the stability of RUVBL1 through methylating its K7 site, aberrantly activating the Wnt/β -catenin signaling pathway to promote tumor stemness. Pemetrexed, a GART -targeting compound, combined with other chemotherapy drugs can suppress tumor growth [1]. In multiple myeloma, GART promotes malignancy via tumor stemness by activating the HSP90α/CDK6/β -catenin axis, and its inhibitor pemetrexed can suppress cell proliferation and tumor growth [4]. In non-small cell lung cancer, GART promotes cell proliferation and migration by targeting the PAICS-Akt-β -catenin pathway [7]. In luminal A ERα-expressing breast cancer, inhibition of GART induces ERα degradation and prevents cell proliferation, and GART inhibitors can be a novel strategy for treating primary and metastatic breast cancers [8].

In Drosophila, Gart is expressed in the glia, fat body, and gut, positively regulating feeding behavior and energy homeostasis [2]. In rat spinal cord injury, GART expression changes dynamically, and its knockdown in astrocytes affects the release of pro-inflammatory factors [3]. In colitis, GART mediates the renewal of the intestinal epithelial barrier via the p38/p53/PUMA cascade [5]. Also, VGLL3 in cancer cells increases the dependency on de novo nucleotide synthesis by inducing GART expression [6].

In conclusion, Gart is crucial for de novo purine biosynthesis and is involved in multiple biological processes and diseases. Studies, including those using potential gene-knockout or other loss-of-function models, have revealed its role in cancer development, feeding behavior, energy homeostasis, inflammation, and epithelial barrier renewal. Targeting Gart shows promise as a therapeutic strategy for several cancers and may offer new insights into treating other related diseases.