The Foxo1-YAP-Notch1 axis reprograms STING-mediated innate immunity in NASH progression

Abstract

Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH. In the battle against nonalcoholic steatohepatitis, it’s vital to understand how our immune system contributes to liver harm. Researchers found that a protein named STING is crucial in liver inflammation and damage as it identifies damaged DNA. They investigate how certain proteins and processes in immune cells affect STING’s function and NASH’s progression. Researchers discovered that decreasing the activity of a protein named Foxo1 in macrophagesresults in less liver damage and inflammation in mice on a high-fat diet. They also examined how other signaling processes, like the Hippo–YAP and Notch1 processes, interact with STING and contribute to the disease. Their findings indicate that adjusting these processes can reduce liver damage, steatosis, and inflammation, suggesting new potential treatment targets for NASH, potentially improving the lives of those affected by this condition.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.