The NF-κB-TNFAIP3 axis attenuates MASLD via activation of hepatocyte autophagy.
- 1Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 2Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
- 3Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
Abstract
Tumor necrosis factor α-induced protein 3 (TNFAIP3) has been implicated in various liver diseases, but its role in metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. We analyzed TNFAIP3 expression in diet-induced MASLD mouse models using public transcriptomic data. In vitro, we investigated the effects of TNFAIP3 overexpression and knockdown in HepG2 cells on lipid accumulation, autophagy, and key metabolic pathways. In vivo, a high-fat diet-induced mouse model was used to validate the protective role of TNFAIP3. TNFAIP3 was consistently upregulated in the livers of various MASLD mouse. Overexpression of TNFAIP3 in HepG2 cells reduced lipid droplet accumulation, whereas knockdown aggravated lipid deposition. TNFAIP3 enhanced autophagy by stabilizing ATG4B, and this effect was autophagy-dependent. In vivo, TNFAIP3 overexpression alleviated hepatic steatosis, improved insulin sensitivity, and modulated lipid metabolism-associated pathways. These effects were reversed by autophagy inhibitors. Furthermore, TNFAIP3 upregulation was driven by NF-κB signaling, as inhibition of NF-κB decreased TNFAIP3 levels. The NF-κB-TNFAIP3 axis regulates hepatic lipid metabolism and protects against liver injury in MASLD, primarily through autophagy. These findings suggest that TNFAIP3 could serve as a potential therapeutic target for MASLD and other metabolic liver diseases.
Related
- Hepatocyte senescence in metabolic dysfunction–associated steatotic liver disease (MASLD)
- Hepatocyte CBX2 Safeguards Hepatic Lipid Homeostasis by Elevating Ca²⁺-CaMKK2-AMPK Signaling to Counter MASLD.
- Hyperactive mTORC1 underlies sex dimorphic progression of MASLD in mice with hepatocyte prohibitin-1 deficiency
- Hepatocyte UBE4A protects against MASLD/MASH by maintaining ER homeostasis via UBXN4 interaction
- Dichloroacetate attenuates experimental acute liver injury and reduces hepatocyte apoptosis
BibTeX
@article{sun2026nfκbtnfaip3,
title = {{The NF-κB-TNFAIP3 axis attenuates MASLD via activation of hepatocyte autophagy.}},
author = {Qun Sun and Guixin Li and Huixiang Yao and Xiangwei Liao and Long Wang and Jinghui Guo},
journal = {Cell death discovery},
year = {2026},
month = aug,
doi = {10.1038/s41420-026-03310-9},
url = {https://europepmc.org/article/MED/42957644},
note = {CC BY},
}
RIS
TY - JOUR
TI - The NF-κB-TNFAIP3 axis attenuates MASLD via activation of hepatocyte autophagy.
AU - Qun Sun
AU - Guixin Li
AU - Huixiang Yao
AU - Xiangwei Liao
AU - Long Wang
AU - Jinghui Guo
PY - 2026
DA - 2026/08/25
JO - Cell death discovery
DO - 10.1038/s41420-026-03310-9
UR - https://europepmc.org/article/MED/42957644
AB - Tumor necrosis factor α-induced protein 3 (TNFAIP3) has been implicated in various liver diseases, but its role in metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. We analyzed TNFAIP3 expression in diet-induced MASLD mouse models using public transcriptomic data. In vitro, we investigated the effects of TNFAIP3 overexpression and knockdown in HepG2 cells on lipid accumulation, autophagy, and key metabolic pathways. In vivo, a high-fat diet-induced mouse model was used to validate the protective role of TNFAIP3. TNFAIP3 was consistently upregulated in the livers of various MASLD mouse. Overexpression of TNFAIP3 in HepG2 cells reduced lipid droplet accumulation, whereas knockdown aggravated lipid deposition. TNFAIP3 enhanced autophagy by stabilizing ATG4B, and this effect was autophagy-dependent. In vivo, TNFAIP3 overexpression alleviated hepatic steatosis, improved insulin sensitivity, and modulated lipid metabolism-associated pathways. These effects were reversed by autophagy inhibitors. Furthermore, TNFAIP3 upregulation was driven by NF-κB signaling, as inhibition of NF-κB decreased TNFAIP3 levels. The NF-κB-TNFAIP3 axis regulates hepatic lipid metabolism and protects against liver injury in MASLD, primarily through autophagy. These findings suggest that TNFAIP3 could serve as a potential therapeutic target for MASLD and other metabolic liver diseases.
SN - 2058-7716
ER -