Reprogrammed Lipid Metabolism as a Gatekeeper of Hepatocarcinogenesis: from Enzyme Regulation to Precision Therapy

Hepatocellular carcinoma (HCC), a lethal malignancy with rising global incidence, is characterized by profound metabolic reprogramming, particularly in lipid metabolism. This process, orchestrated by specialized lipid transporters and key metabolic enzymes, drives tumorigenesis, therapeutic resistance, and immune evasion. The purpose of this review is to integrate the latest mechanistic insights into how these lipid-handling proteins rewire tumor biology and reshape clinical outcomes. Lipid accumulation in hepatocytes serves as a critical driver of hepatocarcinogenesis through the pathological continuum of metabolic-associated fatty liver disease (MAFLD) and steatohepatitis (MASH). These effects are mediated through coordinated pathways: the SEC63-ACLY axis enhances metastasis, FASN confers therapy resistance and immune evasion, and CD36 triggers T cell dysfunction, collectively fueling HCC progression. Notably, the novel anti-CD36 antibody PLT012 demonstrates substantial therapeutic efficacy, highlighting the clinical potential of targeting metabolic-immune crosstalk in HCC. Collectively, these findings establish the hepatic lipid metabolic network as a druggable hub and advocate for synergistic targeting strategies in HCC. This review systematically delineates the lipid transporter and key metabolic enzymes driving hepatic lipid reprogramming in HCC, integrating mechanistic and translational evidence to redefine lipid metabolism as a central therapeutic target. It further evaluates their druggability, proposing precision oncology frameworks to guide HCC treatment strategies.