CDK5RAP3 sustains hepatocyte homeostasis by maintaining glucose metabolism through HSP90AA1

The liver is a central metabolic organ critical for maintaining systemic homeostasis. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3), a substrate of E3 ubiquitin ligases, is involved in diverse signaling pathways and various disease processes; however, its specific role in liver pathology remains poorly understood. Here, we show that hepatocyte-specific deletion of CDK5RAP3 ( CDK5RAP3 Δ/Δhep ) in mice leads to progressive liver disease by five months of age, characterized by hepatocyte apoptosis, cellular hypertrophy, fibrosis, and steatohepatitis. Liver macrophages in CDK5RAP3 Δ/Δhep mice display a shift toward M2 polarization, and metabolomic analyses reveal disrupted hepatic glucose metabolism, including abnormal accumulation of UDP-glucose. Mechanistically, CDK5RAP3 deficiency leads to increased proteasomal degradation of HSP90AA1, which in turn reduces the enzymatic activity of UDP-glucose pyrophosphorylase (UGP2) and phosphoglucomutase 1 (PGM1). Together, these findings identify CDK5RAP3 as a key regulator of hepatic glucose metabolism and underscore its protective role against liver fibrosis and steatohepatitis.