ALDH2 inhibits FASN stabilization via the E3 ligase CBL to suppress lipid accumulation and liver cancer development

Aldehyde dehydrogenase 2 (ALDH2) is implicated in the pathogenesis of multiple diseases. Nevertheless, the biological functions and underlying mechanisms linked to ALDH2 in liver cancer (LC) are not well elucidated. The expression pattern of ALDH2 and its clinical significance in LC were analyzed across multiple cohorts. The interaction between fatty acid synthase (FASN) and ALDH2 was investigated using co-immunoprecipitation (Co-IP) and mass spectrometry (MS). The effects of ALDH2 and casitas B-lineage lymphoma (CBL) on FASN protein stabilization and ubiquitination were evaluated via Co-IP and western blotting. Additionally, the biological roles of ALDH2 in LC cells through FASN inhibition were assessed in both in vitro and in vivo models. Our results showed that ALDH2 expression was downregulated in LC tissues, and this reduction was significantly related to adverse clinical parameters and shorter overall survival in LC patients. FASN, a key enzyme in lipid metabolism, was identified as an interacting partner of ALDH2 in LC cells. Mechanistic studies further revealed that ALDH2 inhibits FASN protein stabilization by enhancing its ubiquitination, thereby reducing FASN protein levels. Bioinformatics analyses and functional experiments confirmed that CBL acts as the E3 ubiquitin ligase for FASN. Importantly, ALDH2 promotes the interaction between CBL and FASN, accelerating FASN degradation. Consequently, ALDH2 suppresses lipid accumulation in LC cells and attenuates LC cell proliferation and migration through FASN inhibition, as validated in vitro and in vivo. Our findings discover a novel mechanism whereby ALDH2 exerts anti-LC effects by inducing FASN ubiquitination and degradation, to decrease lipid accumulation and biological functions in LC cells. Enhancing ALDH2 expression may thus represent a promising therapeutic strategy for LC.