Understanding the Link Between Sterol Regulatory Element Binding Protein (SREBPs) and Metabolic Dysfunction...

This review aims to summarize the current scientific understanding on the complex interplay between sterol regulatory element-binding proteins (SREBPs) and metabolic dysfunction associated steatotic liver disease (MASLD) by critically examining a few significant molecular pathways. Additionally, the review explores the potential of both natural and synthetic SREBP inhibitors as promising therapeutic candidates for MASLD.

SREBPs are central regulators of lipid homeostasis, with SREBP-1c primarily controlling fatty acid synthesis and SREBP-2 regulating cholesterol metabolism. Dysregulation of SREBP activity, often triggered by excessive caloric intake, insulin resistance, or endoplasmic reticulum (ER) stress, contributes to the development of metabolic syndrome and MASLD. SREBP-1c overexpression leads to increased de novo lipogenesis (DNL), hepatic lipid accumulation, and insulin resistance, while SREBP-2 modulates cholesterol metabolism via miRNA-33 and ABCA1 regulation leading to the pathogenesis of MASLD. The PI3K-Akt-mTORC1 pathway plays a critical role in SREBP activation, linking nutrient availability to lipid synthesis. Synthetic SREBP inhibitors, such as fatostatin and 25-hydroxycholesterol, and natural compounds, including kaempferol and resveratrol, show promise in modulating SREBP activity in vivo.

While targeting SREBP pathways presents a promising avenue for mitigating MASLD, further scientific investigation is imperative to identify and validate potential molecular targets. Although current studies on synthetic and natural SREBP inhibitors demonstrate encouraging results, rigorous pre-clinical and clinical research is warranted to translate these findings into effective MASLD treatments.