Hepatocyte FoxO1 depletion exacerbates hepatic inflammation in MASH by targeting cystathionine γ-lyase

• Published in: Scientific reports Vol. 15; no. 1; pp. 26631 - 12
• Main Authors: Chen, Hui-Ting, Huang, Chen, Chen, Jia-Wei, Yang, Si-Qi, Cheng, Jie-Min, Li, Yong-Qiang, Chen, Han-Qing, Zhou, Yong-Jian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 692/4020; 692/699; Animals; Biotechnology; CTH; Cystathionine g-lyase; Cystathionine gamma-Lyase - genetics; Cystathionine gamma-Lyase - metabolism; Feeds; Forkhead Box Protein O1 - deficiency; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Forkhead protein; FoxO1; FOXO1 protein; Genes; Glucose metabolism; Hepatocyte; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Humanities and Social Sciences; Inflammation; Inflammation - metabolism; Inflammation - pathology; L-Alanine; Life sciences; Lipid metabolism; Lipopolysaccharides; Liver; Liver - metabolism; Liver - pathology; Liver diseases; Male; MASH; Metabolism; Metabolites; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Nutrient deficiency; Polymerase chain reaction; Proteins; Reagents; Science; Science (multidisciplinary); Therapeutic targets; Transcriptomics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; United States > US; China; Japan; MASH; Inflammation; Hepatocyte; CTH; FoxO1
• DOI: 10.1038/s41598-025-10192-x
• ISSN: 2045-2322

The transcription factor Forkhead box protein O1 (FoxO1) is a well-established regulator of glucose and lipid metabolism, yet its role in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis remains debated. This study investigates hepatocyte-specific FoxO1 mechanisms driving hepatic inflammation in MASH. Using hepatocyte-specific FoxO1-knockout (KO) mice fed a methionine-choline-deficient diet and LPS-treated FoxO1-KO cells, we demonstrated that FoxO1 depletion exacerbates hepatic inflammation, ballooning degeneration, and upregulates TNF-α, CXCL8, and CXCL2 in vivo and in vitro. Transcriptomic analysis revealed that FoxO1 deficiency upregulated pro-inflammatory pathways while suppressing cysteine/methionine metabolism, with a notable reduction in cystathionine γ-lyase (CTH) expression. Luciferase assays confirmed that FoxO1 directly binds the CTH promoter. In MASH mice, reduced CTH levels correlated with elevated TNF-α/CXCL8. Pharmacological CTH inhibition via β-cyano-L-Alanine (BCA) amplified LPS-induced inflammation in THLE-2 cells, while CTH overexpression rescued inflammatory responses in FoxO1-deficient hepatocytes. Our findings unveil FoxO1 as a transcriptional activator of CTH, coupling metabolic adaptation to inflammatory regulation in MASH, and propose the FoxO1-CTH axis as a therapeutic target for inflammatory liver disease.