Development of retinoid nuclear receptor pathway antagonists through targeting aldehyde dehydrogenase 1A3.

ABSTRACT: Aldehyde dehydrogenase 1a3 (ALDH1A3) activity is recognized as a pathogenic trait in cardiometabolic diseases and cancer, though the mechanisms by which ALDH1A3 promotes disease are unclear and effective therapeutic inhibitors of ALDH1A3 are lacking. Whereas the function of the ALDH1A enzymes in development is the conversion of retinaldehyde into all-trans retinoic acid (atRA) to activate retinoid nuclear receptor signaling, this pathway is paradoxically hypothesized as a cell-intrinsic tumor suppressor pathway. We resolve this paradox by showing that while ALDH1A3 is overexpressed across diverse cancers, ALDH1A3-expressing tumor cells lose sensitivity to retinoid signaling. Instead, atRA produced by ALDH1A3 acts in a paracrine fashion to activate retinoid nuclear receptor signaling

SUBMITTER: Esposito M 

PROVIDER: S-EPMC12595434 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature