Targeting CREB3L2-mediated lipid metabolism overcomes lenvatinib resistance and attenuates the progression of hepatocellular carcinoma.

When hepatocellular carcinoma (HCC) cells exhibit malignant biological behaviors, lipid metabolic reprogramming occurs concomitantly. Thus, identifying regulators of metabolic reprogramming offers new potential targets for therapy. In this study, we investigated the mechanisms by which Cyclic adenosine monophosphate-responsive element binding protein 3-like 2(CREB3L2) influences HCC progression and contributes to lenvatinib resistance through modulation of lipid metabolism. Up-regulated expression of CREB3L2 was observed in numerous HCC cohorts and associated with poor survival prognosis of patients. Furthermore, CREB3L2 could facilitate the proliferation and metastatic capacity of HCC cells both in vitro and in vivo. It was found that CREB3L2 influences the proliferation and metastasis of HCC cells by up-regulating sterol regulatory element binding protein 1 (SREBP1), a vital regulatory factor of lipid synthesis for fatty acid production. Additionally, CREB3L2 enhances SREBP1 protein expression and stability through increased acetylation mediated by histone acetyltransferase-1(HAT1). Importantly, targeting CREB3L2 in combination with lenvatinib significantly reduced lenvatinib resistance, inhibiting the progression of CREB3L2 high-expressing HCC tumors. These findings suggest that the CREB3L2/HAT1/SREBP1 regulatory axis drives lenvatinib resistance and HCC progression by impacting lipid metabolism. Targeting CREB3L2 alongside lenvatinib improves the efficacy of treating HCC.