ANKRD9 (ankyrin repeat domain 9) functions as a substrate receptor subunit of a CUL5-based E3 ubiquitin ligase complex that mediates proteasomal degradation of target proteins 1. A primary substrate is IMPDH2, the rate-limiting enzyme in GTP biosynthesis; however, ANKRD9's regulation of IMPDH2 is metabolically controlled and context-dependent 2. Under basal conditions, ANKRD9 is sequestered in vesicular structures, but upon nutrient limitation, it assembles with IMPDH2 into stabilizing filaments, protecting IMPDH2 from degradation 2. ANKRD9 also couples ATP synthesis to lipoprotein trafficking in enterocytes, regulating purine biosynthesis pathway enzymes and Golgi dynamics to facilitate dietary fat absorption 3. Beyond metabolism, ANKRD9 exhibits tumor-suppressive activity; its depletion accelerates proliferation and anchorage-independent growth of gastric cancer cells, and genetic variants associate with gastric cancer susceptibility 1. ANKRD9 is implicated in copper homeostasis and has been identified as a hub gene in type 2 diabetes with depression comorbidity, where it is significantly downregulated 4. DNA methylation alterations in ANKRD9 are associated with maternal smoking exposure and post-COVID-19 infection, suggesting epigenetic involvement in disease pathogenesis 56. These findings position ANKRD9 as a metabolically-sensitive regulator with broad implications for cancer, metabolic disease, and immune response.