The SEMA7A^N559Y mutation facilitates the development of metabolic dysfunction-associated steatotic liver disease by...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition that can result in significant liver damage. This study aimed to evaluate the effects of the SEMA7A^N559Y mutation on MASLD progression and to explore potential therapeutic targets.

To examine the impact of the SEMA7A^N559Y mutation on MASLD progression, we generated Sema7a^N557Y (equal to human SEMA7A^N559Y) heterozygous mutant mice. At 8 weeks old, both wild-type and Sema7a^N557Y heterozygous mice were placed on a high-fat diet. After dietary intervention, mice were euthanized, and serum and liver tissues were collected for analysis. The effects of the SEMA7A^N559Y mutation on MASLD progression were assessed using biochemical assays, histological analysis, and Western blotting.

The Sema7a^N557Y mutation worsened lipid metabolism disorders, causing hepatic steatosis, inflammation, and fibrosis in mice fed a high-fat diet. The SEMA7A^N559Y mutation strengthens its interaction with integrin β1, triggering the PI3K/Akt pathway and increasing ROS production, which leads to hepatic oxidative stress and NLRP3 inflammasome activation.

The N559Y variant in SEMA7A suggests a potential association with exacerbated hepatic oxidative stress, heightened pyroptosis, and increased MASLD severity. Targeting the SEMA7A-integrin β1 interaction could represent a potential novel therapeutic approach.