The role of SAC1-mediated macrophage NLRP3 inflammasome activation in the progression of MASH inflammation
10.19405/j.cnki.issn1000-1492.2026.08.001
- VernacularTitle:SAC1介导的巨噬细胞NLRP3炎症小体激活在MASH炎症进展中的作用
- Author:
Zhiyang SUN
1
;
Xinwang CAO
1
Author Information
1. Department of Cell Biology， School of Life Sciences， Anhui Medical University， Hefei 230032
- Publication Type:Journal Article
- Keywords:
SAC1;
MASH;
NLRP3 inflammasome;
dispersed trans-Golgi network;
p65
- From:
Acta Universitatis Medicinalis Anhui
2026;61(8):1333-1341
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate the molecular mechanism by which SAC1-like phosphatidylinositide phosphatase （SAC1） regulates NOD-like receptor protein 3 （NLRP3） inflammasome activation in macrophages and to explore its role in the pathological progression of metabolic dysfunction-associated steatohepatitis （MASH）. MethodsSingle-cell RNA sequencing （scRNA-seq） was utilized to analyze the differential expression levels of SACM1L in liver macrophage subpopulations between control and MASH mice. Bone marrow-derived macrophages （BMDMs） from control and high-fat diet-fed mice were isolated and cultured， and the expression levels of SACM1L and NLRP3 were determined via RT-qPCR and Western blot. CRISPR/Cas9 technology was employed to establish SACM1L-knockout THP-1 macrophage and HeLa cell lines. The phosphorylation of p65 and the activation status of the NLRP3 inflammasome were compared between wild-type and SACM1L-knockout THP-1 cells. Immunofluorescence assays were conducted to evaluate the spatial recruitment capacity of NLRP3 to the dispersed trans-Golgi network （dTGN） in wild-type and SACM1L-knockout HeLa cells. Furthermore， a MASH mouse model was established by feeding mice a choline-deficient high-fat diet containing 0.1% methionine （CDA-HFD） for 10 weeks， and the expression levels of SACM1L and NLRP3 in liver tissues were compared between the control and MASH groups. ResultsBioinformatics analysis and in vivo experiments consistently demonstrated that the expression levels of SACM1L and NLRP3 were significantly upregulated in both liver tissues and macrophages of MASH mice. SACM1L deficiency attenuated the increase in p-p65 levels induced by tripalmitoyl cysteinyl seryl tetra-lysine （Pam3CSK4）， inhibited the spatial recruitment of NLRP3 to the dTGN， and attenuated the subsequent maturation and release of downstream Caspase-1 and IL-1β. ConclusionSAC1 promotes NLRP3 expression by facilitating p65 signaling activation and mediates the spatial recruitment of NLRP3 to the dTGN. This process exacerbates the macrophage inflammatory response， thereby accelerating the pathological progression of MASH.
