Acute liver failure is regulated by MYC- and microbiome-dependent programs

Area of Science:

• Hepatology and Immunology
• Single-cell Transcriptomics
• Microbiome Research

Background:

• Acute liver failure (ALF) is a severe condition with high mortality, primarily managed with supportive care and liver transplantation.
• Current treatment options for ALF are limited, highlighting the need for novel therapeutic strategies targeting underlying mechanisms.

Purpose of the Study:

• To create a comprehensive cellular atlas of ALF using single-cell transcriptomics in mouse models.
• To identify novel cell subsets and intercellular communication networks driving ALF pathogenesis.
• To elucidate conserved molecular pathways, such as MYC signaling, involved in ALF and explore therapeutic interventions.

Main Methods:

• Characterization of 56,527 single-cell transcriptomes from acetaminophen (APAP) and thioacetamide (TAA) induced ALF mouse models.
• Identification of distinct cell subsets (stellate, endothelial, Kupffer, monocytes, neutrophils) and their interactions.
• Analysis of MYC-dependent transcriptional programs and their regulation by the gut microbiome via Toll-like receptor (TLR) signaling.

Main Results:

• Discovery of unique, previously uncharacterized cell subsets and their complex crosstalk contributing to ALF.
• Unraveling of a common MYC-dependent transcriptional program coordinating stellate, endothelial, and Kupffer cell activation in ALF.
• Demonstration that gut microbiome modulation and pharmacological inhibition of MYC or TLR signaling attenuate ALF in mice.
• Confirmation of upregulated hepatic MYC expression in human ALF patients compared to healthy donors.

Conclusions:

• Detailed cellular and genetic decoding of ALF reveals critical cell subsets and pathways driving the disease.
• The gut microbiome and MYC signaling represent key regulatory nodes in ALF pathogenesis.
• Targeting MYC, TLR signaling, or the gut microbiome offers a promising avenue for developing novel ALF therapeutics.