Aldehydes alter TGF-β signaling and induce obesity and cancer

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD and MASH) affect over a 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+/- (ASKO) mice develop phenotypes of human Metabolic Syndrome (MetS) and MASH with altered lipid metabolism and TGF-β signaling, leading to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal with siRNA to SPTBN1. Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human 3D MASH model. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target. Using unbiased transcriptome methods snRNA-seq and RNA-seq to characterize liver metabolism alterations in mice (WT, Sptbn1+/-, Aldh2-/-, Aldh2-/-Sptbn1+/-) under normal chow diet. Using bulk RNA-seq analysis of human 3D MASH coculture cells to explore the therapeutic effects of targeting Sptbn1.

肥胖及脂肪性肝病——包括代谢功能障碍相关脂肪性肝病（metabolic dysfunction-associated steatotic liver disease, MASLD）与代谢功能障碍相关脂肪性肝炎（metabolic dysfunction-associated steatotic hepatitis, MASH）——影响全球超过三分之一的人口；而功能性乙醛脱氢酶2（aldehyde dehydrogenase 2, ALDH2）活性降低的人群患病后病情会进一步加重，这类人群全球约有5.6亿。当前尚无足够有效的治疗手段可阻止疾病进展为癌症，亟需探索创新治疗策略。本研究发现，醛脱氢酶2敲除（Aldh2-/-）小鼠与醛脱氢酶2敲除兼血影蛋白β1单倍体不足（Aldh2-/-Sptbn1+/-，简称ASKO）小鼠可出现人类代谢综合征（Metabolic Syndrome, MetS）与MASH的表型，伴随脂质代谢与转化生长因子β（transforming growth factor-β, TGF-β）信号通路异常，最终促发促纤维化与促肿瘤发生表型；而通过靶向SPTBN1的小干扰RNA（small interfering RNA, siRNA）干预可使上述表型恢复正常。值得注意的是，在人类3D MASH模型中，靶向抑制SPTBN1可阻断MASH进展与肝纤维化发生。本研究证实SPTBN1是毒性醛诱导型MASH功能表型的关键调控因子，同时也是潜在的治疗靶点。本研究采用无偏倚转录组学方法，即单细胞核RNA测序（single nuclear RNA sequencing, snRNA-seq）与RNA测序（RNA sequencing, RNA-seq），对正常普通饲料喂养的小鼠（野生型（wild type, WT）、Sptbn1+/-单倍体不足型、Aldh2-/-敲除型、Aldh2-/-Sptbn1+/-双突变型）的肝脏代谢改变进行表征。此外，本研究通过对人类3D MASH共培养细胞进行批量RNA测序（bulk RNA-seq）分析，探究靶向SPTBN1的治疗效果。