Ubiquitination of TFEB increased intestinal permeability to aggravate metabolic dysfunction–associated steatohepatitis

Background and Aims: Increased intestinal permeability exacerbates the development of metabolic dysfunction–associated steatohepatitis (MASH), but the underlying mechanisms remain unclear. Autophagy is important for maintaining normal intestinal permeability. Here, we investigated the impact of intestinal transcription factor EB (TFEB), a key regulator of autophagy, on intestinal permeability and MASH progression. Approach and Results: TFEB expression was analyzed in the proximal colon of 45 individuals with metabolic dysfunction–associated steatotic liver disease and 23 healthy controls. We used immunoprecipitation-mass spectrometry to identify TFEB-interacting proteins. Intestine-specific Tfeb knockout mice were generated by mating Tfeb fl/fl mice with Villin- Cre mice. The mice were fed a high-fat, high-sucrose diet, and assessments were performed to evaluate intestinal permeability and MASH progression. Intestinal TFEB levels were reduced in patients with MASH and negatively correlated with intestinal permeability and hepatic toxicity. Intestine-specific TFEB deficiency increased intestinal permeability and worsened MASH severity, whereas moderate TFEB overexpression conferred protective effects. Mechanistically, the E3 ligase TRIP12 promotes the ubiquitination and degradation of nuclear TFEB, thereby inhibiting autophagic flux to aggravate intestinal barrier impairment and subsequently promote MASH progression. Importantly, a peptide PT1 designed to block the TRIP12-TFEB interaction reduced MASH progression. Conclusions: The ubiquitination of TFEB plays a pivotal role in increasing intestinal permeability and promoting the progression of MASH by inhibiting autophagy. Intestinal TFEB may represent a novel therapeutic target for the treatment of MASH.