Nakagawa Hayato
Department of Gastroenterology and Hepatology, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Arch Toxicol. 2025 May 6. doi: 10.1007/s00204-025-04052-w.
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.
代谢功能障碍相关脂肪性肝病（MASLD）是全球最常见的慢性肝病，也是肝细胞癌（HCC）的主要危险因素。脂质代谢，特别是由固醇调节元件结合蛋白（SREBPs）调控的从头脂肪生成（DNL），在MASLD进展中起关键作用。虽然SREBP过度激活会导致肝脏脂肪变性，但我们最近的研究结果表明，在小鼠MASLD模型中，强烈抑制SREBP反而会加剧肝损伤并加速致癌作用。从机制上讲，SREBP功能障碍会破坏磷脂稳态，导致内质网（ER）膜流动性受损、ER应激和肝细胞损伤。对临床样本的转录组分析揭示了SREBP活性的动态变化，在早期MASLD中上调，但在晚期、衰竭的MASH中显著下调。这表明晚期疾病中的SREBP功能障碍可能导致纤维化进展和HCC风险增加。鉴于这些发现，针对MASLD脂质代谢的治疗策略必须根据疾病阶段进行精心调整。本综述提供了关于SREBP在MASLD中双相作用的最新观点，强调需要重新思考针对脂质代谢的治疗方法，并开发个性化干预措施以减轻疾病进展和HCC发展。
