Sterol regulatory element-binding protein pathway (SREBP pathway)

The Sterol Regulatory Element-Binding Protein (SREBP) pathway is a master regulatory system for lipid homeostasis in mammalian cells, comprising isoforms SREBP-1a, SREBP-1c, and SREBP-2 (Horton et al., 2002, J. Clin. Invest.). These proteins are synthesized as inactive precursors in the endoplasmic reticulum (ER) and require translocation to the Golgi for proteolytic activation by Site-1 and Site-2 proteases when sterol levels are low. Once activated, the N-terminal domain enters the nucleus to drive the transcription of genes essential for cholesterol and fatty acid synthesis. Dysregulation of this pathway is central to the pathogenesis of metabolic diseases like non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia, as well as various cancers that rely on de novo lipogenesis for rapid proliferation (Guo et al., 2014, Cancer Metab.). Pharmacological targeting of the SREBP pathway, through small molecules like Fatostatin or S1P inhibitors, aims to reduce lipid accumulation and inhibit tumor growth by disrupting this critical metabolic switch.

Other names

SREBP signaling pathwaySterol regulatory element-binding transcription factor pathwaySREBP-SCAP-S1P-S2P axis

Inhibition of the proteolytic activation of SREBP precursors, primarily by blocking the SCAP-mediated transport from the endoplasmic reticulum to the Golgi apparatus or inhibiting the Site-1 (S1P) and Site-2 (S2P) proteases (Horton et al., 2002; Kamisuki et al., 2009).