Animal models reveal TTC39B influences hepatic lipogenesis via VAPB/SCAP interaction; the SphK2-CERT axis promotes ceramide conversion to sphingomyelin (SM), driving NAFLD-HCC progression. In vitro reconstitution studies confirm ORP/OSBP sterol transport relies on PI4P gradients. Its core role in hepatic lipogenesis awaits further validation in animal models. Here, TTC39B is linked to hepatocellular carcinoma.