Mice generate 5β-reduced glucocorticoid metabolites (Shackleton et al. 2008), and AKR1D1 controls glucocorticoid availability and action in human hepatoma cell lines (Nikolaou et al. 2019a); nevertheless, circulating corticosterone levels were normal in Akr1d1–/– mice and hepatic expression of glucocorticoid-regulated genes was unchanged. Here, AKR1D1 is linked to hepatocellular carcinoma.