Metabolic reprogramming is a hallmark of cancer and a driver of hepatocellular carcinoma (HCC) initiation and progression. Through metabolic CRISPR screening, we identify phosphomevalonate kinase (PMVK), a critical kinase in the mevalonate pathway, as a key regulator in HCC stemness and lipid metabolism. Mechanistically, PMVK directly phosphorylates the transcription factor SP1 at Thr355, enhancing its DNA-binding affinity to increase transcriptional activity to promote the expression of genes involved in de novo lipid synthesis. Phosphorylated SP1 directly interacts with nuclear SREBP1/2, master factors of lipid biosynthesis, and facilitates the transcription of their target genes. Clinically, elevated levels of PMVK and phospho-SP1 (Thr355) are associated with poor prognosis in HCC patients. Functionally, genetic or pharmacologic inhibition of PMVK or SP1 significantly suppress HCC growth in cell lines, mouse models, and patient-derived organoids. These findings uncover a previously unrecognized PMVK–SP1 ax