The METTL3/TRIM37 axis contributes to the progression of non-alcoholic fatty liver disease by promoting CAV1 degradation.

Caveolin-1 (CAV1), a principal structural component of caveolae, plays a pivotal role in the regulation of lipid metabolism, signal transduction, and cellular homeostasis. Dysregulation of CAV1 has been implicated in the pathogenesis of metabolic diseases, particularly non-alcoholic fatty liver disease (NAFLD). However, the precise molecular mechanisms responsible for CAV1 in NAFLD remain largely unclear. In vitro experiments were performed using THLE-3 or HepG2 cells treated with palmitic acid (PA) to establish a lipotoxic model. Quantitative real-time polymerase chain reaction was used to detect mRNA levels, whereas western blotting was performed to analyze protein expression. Cell viability, proliferation, apoptosis, and lipid deposition were assessed using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, and Oil Red O staining, respectively. Ferroptosis was evaluated by measuring Fe2+ levels, malondialdehyde (MDA), superoxide dismutase (SOD), and lipid peroxidation. Molecular interactions, including ubiquitination, co-immunoprecipitation (Co-IP), methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and dual-luciferase reporter assays, were used to analyze the association among m6A methyltransferase-like 3 (METTL3), tripartite motif containing 37 (TRIM37) and CAV1. An in vivo NAFLD model was generated in mice fed a high-fat diet (HFD). In the animal study, liver injury and steatosis were visualized by hematoxylin and eosin (H&E) and Oil Red O staining. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as hepatic triglyceride (TG) and total cholesterol (TC) levels, were quantified to assess liver function and lipid accumulation. CAV1 expression was downregulated in blood samples of NAFLD patients. PA treatment significantly downregulated CAV1 expression, inhibited cell proliferation, increased apoptosis, and enhanced ferroptosis and lipid deposition; however, all of which were significantly reversed by CAV1 overexpression. Mechanistically, the E3 ubiquitin ligase TRIM37 was identified as a negative regulator of CAV1; TRIM37 was found to interact with CAV1 and promote its ubiquitination and degradation. Furthermore, METTL3 upregulated TRIM37 expression by binding to its mRNA transcript in an IGF2BP1-dependent manner, thereby enhancing TRIM37 mRNA stability. Knockdown of TRIM37 or METTL3 mitigated PA-induced cellular damage, but these protective effects were abolished by CAV1 silencing or TRIM37 overexpression, respectively. Consistent with the in vitro findings, in vivo experiments confirmed that CAV1 overexpression attenuated HFD-induced liver injury. This study unveils a novel METTL3/TRIM37/CAV1 regulatory axis that represents an important pathway contributing to NAFLD exacerbation. Restoring CAV1 expression represents a promising therapeutic strategy for NAFLD.