The depletion of serine beta-lactamase-like protein (LACTB) ameliorates metabolic dysfunction-associated steatotic liver disease by reducing ubiquitin-mediated degradation of carnitine palmitoyltransferase 2.

PubMed1 Apr 2026·Diabetes, obesity & metabolism● 4/10i

The depletion of serine beta-lactamase-like protein (LACTB) ameliorates metabolic dysfunction-associated steatotic liver disease by reducing ubiquitin-mediated degradation of carnitine palmitoyltransferase 2.

Shi W, Liu X, Wang N, Zhang Q, Gao J et al.

LACTB protein levels were elevated in liver tissues from patients with MASLD and high-fat diet mice, with LACTB depletion improving hepatic steatosis, insulin resistance, and inflammation. Preclinical study using patient samples and mouse models with in vitro validation. This identifies a novel therapeutic target mechanism for MASLD through CPT2-mediated fatty acid oxidation, providing new pathway understanding for a disease affecting over 25% of the global population. Early-stage target discovery without established drug development programs.

Strategic signal

This target discovery positions LACTB as a novel NASH/MASLD therapeutic pathway, potentially offering differentiation from current approaches focused on FXR agonists and GLP-1s. Given Roche's recent $3.1B Telavant acquisition and ongoing investments by Madrigal, Intercept, and others in NASH programs, this mechanism could attract biotech partnerships or acquisitions. However, the mitochondrial target location presents significant drug development challenges that may limit commercial viability compared to established pathways.

Liver/NASHMechanisms

Original Abstract

AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents one of the most common chronic liver disorders worldwide, and its incidence continues to rise each year. Serine β-lactamase-like protein (LACTB) is a serine protease that plays a crucial role in lipid metabolism and hepatocellular carcinoma, but its function in MASLD remains unclear. Therefore, the study aims to elucidate the effect and mechanism of LACTB in the progression of MASLD. MATERIALS AND METHODS: The expression of LACTB in liver tissues from MASLD patients and high-fat diet (HFD) fed mice was assessed. Both in vivo and in vitro models were established to examine the role and molecular mechanisms of LACTB in MASLD. RESULTS: LACTB protein levels were upregulated in the liver tissues from MASLD patients and HFD-fed mice. LACTB overexpression exacerbated hepatic steatosis, insulin resistance, and inflammation in HFD-fed mice. Conversely, LACTB knockdown improved these phenotypes. Mechanistically, LACTB interacted with CPT2 and promoted its ubiquitin-mediated degradation. The effect of LACTB in hepatocellular lipid metabolism was dependent on CPT2. CONCLUSIONS: Our findings indicate that LACTB is a novel regulatory factor in MASLD by influencing the ubiquitin-mediated degradation of CPT2 to participate in disease progression. These findings may provide a novel potential therapeutic strategy for MASLD.

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