Aldehydes alter TGF-b signaling and induce obesity and cancer

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 b (TGF-b) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (b2-spectrin) to pro
fibrotic and pro-oncogenic phenotypes, which is restored to normal with small interfering RNA (siRNA) to
SPTBN1. 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.