We demonstrated that genetic and pharmacological inhibition of DHCR7 suppresses steatosis, inflammation, fibrosis, and HCC in DEN-challenged HFD + EtOH-fed mice or 3D human liver spheroids, which mimic “MetALD in a dish.” Reducing DHCR7 expression and activity in tumors or the tumor microenvironment ameliorated MetALD, suggesting that targeting cholesterol synthesis can become a novel strategy for the treatment of MetALD and HCC. Here, DHCR7 is linked to neoplasm.