肥胖和脂肪肝疾病——代谢功能障碍相关的脂肪性肝病 (MASLD) 和代谢功能障碍相关的脂肪性肝炎 (MASH)——影响着全球三分之一以上的人口，并且在功能性乙醛脱氢酶 2 (ALDH2) 降低的个体中恶化。在大约 5.6 亿人中观察到。目前预防疾病进展为癌症的治疗方法仍然不足，需要创新方法。我们观察到 Aldh2-/- 和 Aldh2-/-Sptbn1 /- 小鼠随着 4-羟基壬烯醛 (4-HNE) 等内源醛的积累而出现人类代谢综合征 (MetS) 和 MASH 的表型。机制研究表明，通过 SMAD3 接头 SPTBN1（β2-血影蛋白）的 4-HNE 修饰，异常转化生长因子 β (TGF-β) 信号转导可产生促纤维化和促癌表型，通过靶向 SPTBN1 可恢复正常 SMAD3 信号转导小干扰RNA (siRNA)。值得注意的是，治疗性抑制 SPTBN1 可阻断人类模型中的 MASH 和纤维化，此外还可以改善 Aldh2-/- 和 Aldh2-/-Sptbn1/- 小鼠的葡萄糖处理能力。这项研究将 SPTBN1 确定为有毒醛诱导的 MASH 功能表型的关键调节因子和潜在的治疗靶点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.