TMEM189/PEDS1 deficiency aggravates MASH progression by promoting FASN-mediated macrophage activation
4 affiliations
- 1Department of Immunology, School of Basic Medical Sciences Peking University; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
- 2Department of General Surgery, Beijing Electric Power Hospital, State Grid Corporation of China; Clinical Medical Research Center for Hepatobiliary Diseases in General Surgery, China General Technology Group, Beijing, China
- 3Medical and Healthy Analytical Center, Peking University, Beijing, China
- 4Center for Human Disease Genomics, Peking University, Beijing, China
Abstract
Transmembrane protein 189 (TMEM189), also known as plasmanylethanolamine desaturase 1 (PEDS1), is involved in plasmalogen biosynthesis, phospholipid metabolism, ferroptosis, and autophagy. However, whether TMEM189/PEDS1 regulates macrophages and disease-related inflammatory responses remains unclear. Here, we for the first time investigated the contribution of TMEM189/PEDS1 to macrophage activation and progression of metabolic dysfunction-associated steatohepatitis (MASH). Experimental data demonstrated that TMEM189 is highly expressed in macrophages, and its inactivation promotes M1 macrophage polarization and increases lipid loading in co-cultured hepatocytes. Loss of Tmem189 in myeloid cells results in a selective increase in the population and activation of monocyte-derived macrophages (MDMs) in the liver, which exacerbates hepatic steatosis, inflammatory damage, and fibrosis in diet-induced MASH mice. The restoration of Tmem189 expression in hepatic macrophages significantly attenuates MASH-related phenotypes. Mechanistically, TMEM189 interacts with fatty acid synthase (FASN), negatively regulates its expression and pro-inflammatory response in macrophages. Further studies revealed that TMEM189 deletion enhances FASN-promoted NLRP3 palmitoylation and its activation, leading to increased IL-1β production, which in turn further accelerates MASH progression. Our findings provide important evidence supporting the critical regulatory role of TMEM189-FASN signaling in liver macrophage activation and MASH progression, which may represent a potential therapeutic target for MASH treatment.
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BibTeX
@article{guo2026tmem189peds1,
title = {{TMEM189/PEDS1 deficiency aggravates MASH progression by promoting FASN-mediated macrophage activation}},
author = {Pengli Guo and Jinqiu Feng and Yaxin Lou and Tao Li and Shufang Ye and Yongjun Zhang and Chunlei Wang and Ping Lv and Zongming Zhang and Yingyu Chen},
journal = {Cell Death \& Disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09145-7},
url = {https://doi.org/10.1038/s41419-026-09145-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TMEM189/PEDS1 deficiency aggravates MASH progression by promoting FASN-mediated macrophage activation
AU - Pengli Guo
AU - Jinqiu Feng
AU - Yaxin Lou
AU - Tao Li
AU - Shufang Ye
AU - Yongjun Zhang
AU - Chunlei Wang
AU - Ping Lv
AU - Zongming Zhang
AU - Yingyu Chen
PY - 2026
DA - 2026/08/13
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09145-7
UR - https://doi.org/10.1038/s41419-026-09145-7
AB - Transmembrane protein 189 (TMEM189), also known as plasmanylethanolamine desaturase 1 (PEDS1), is involved in plasmalogen biosynthesis, phospholipid metabolism, ferroptosis, and autophagy. However, whether TMEM189/PEDS1 regulates macrophages and disease-related inflammatory responses remains unclear. Here, we for the first time investigated the contribution of TMEM189/PEDS1 to macrophage activation and progression of metabolic dysfunction-associated steatohepatitis (MASH). Experimental data demonstrated that TMEM189 is highly expressed in macrophages, and its inactivation promotes M1 macrophage polarization and increases lipid loading in co-cultured hepatocytes. Loss of Tmem189 in myeloid cells results in a selective increase in the population and activation of monocyte-derived macrophages (MDMs) in the liver, which exacerbates hepatic steatosis, inflammatory damage, and fibrosis in diet-induced MASH mice. The restoration of Tmem189 expression in hepatic macrophages significantly attenuates MASH-related phenotypes. Mechanistically, TMEM189 interacts with fatty acid synthase (FASN), negatively regulates its expression and pro-inflammatory response in macrophages. Further studies revealed that TMEM189 deletion enhances FASN-promoted NLRP3 palmitoylation and its activation, leading to increased IL-1β production, which in turn further accelerates MASH progression. Our findings provide important evidence supporting the critical regulatory role of TMEM189-FASN signaling in liver macrophage activation and MASH progression, which may represent a potential therapeutic target for MASH treatment.
SN - 2041-4889
ER -