Lipogenesis and MASLD: re-thinking the role of SREBPs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and a major risk factor for hepatocellular carcinoma (HCC). Lipid metabolism, particularly de novo lipogenesis (DNL) regulated by sterol regulatory element-binding proteins (SREBPs), plays a key role in MASLD progression. While excessive SREBP activation contributes to hepatic steatosis, our recent findings indicate that strong SREBP inhibition paradoxically exacerbates liver injury and accelerates carcinogenesis in murine MASLD models. Mechanistically, SREBP dysfunction disrupts phospholipid homeostasis, leading to impaired endoplasmic reticulum (ER) membrane fluidity, ER stress, and hepatocyte injury. Transcriptomic analysis of clinical samples revealed a dynamic shift in SREBP activity, with upregulation in early MASLD but significant downregulation in advanced, burned-out MASH. This suggests that SREBP dysfunction in advanced disease may contribute to fibrosis progression and increased HCC risk. Given these findings, therapeutic strategies targeting lipid metabolism in MASLD must be carefully tailored to disease stage. This review provides an updated perspective on the biphasic role of SREBP in MASLD, emphasizing the need to re-think lipid metabolism-targeted therapies and develop personalized interventions to mitigate disease progression and HCC development.