Aldehydes alter TGF-ß 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-ß 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. Overall design: 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.