EASL 2025 YAQ005 + YAQ007: Transcriptomic and metabolic insights into hyperammonemia

• Hyperammonemia is a critical issue in patients with liver diseases, where elevated ammonia levels predict mortality and a reduction in ammonia levels is linked to improved survival. • Despite this, no effective therapies are available, highlighting an unmet clinical need. • Previous studies have identified toll-like receptor 4 (TLR4) as a potential therapeutic target for hyperammonemia by modulating mitochondrial function1,2. Contact informationReferences Introduction Methods Transcriptomic and metabolic insights into hyperammonemia : Supachaya Sriphoosanaphan, M.D., M.Sc. Email: [email protected] • A mouse model of chronic hyperammonemia (WT and TLR4KO) was studied1,2. • Ammonia levels were significantly elevated in WT-AA mice and both TAK-242 and OP treatment effectively reduced ammonia levels. • Liver transcriptomic analysis was performed using RNA sequencing to investigate key metabolic pathways, including the urea cycle, tricarboxylic acid cycle, oxidative phosphorylation (OXPHOS) complexes, and oxidative stress pathways. TLR4KO mice exhibited gene expression changes consistent with a combined effect of TAK-242 and OP treatment. Main findings Conclusions Aim • To explore the therapeutic potential of TLR4 antagonist (TAK-242) and the ammonia scavenger Ornithine Phenylacetate (OP) through transcriptomic analysis to identify pathways for targeted treatment strategies. Both TAK-242 and OP treatment reverted Cox6b2 and Glul expression. Additionally, Cox7a1 was downregulated in the TAK-242 group, while Oscp1 was downregulated in the OP group indicating distinct mechanisms of action for each treatment. the complementary therapeutic roles of toll -like receptor 4 inhibitor and ornithine phenylacetate Supachaya Sriphoosanaphan1,2,3, Francesco De Chiara4, Annarein Kerbert1, Abeba Habtesion1, Fausto Andreola1, Gautam Mehta1, Rajiv Jalan1 1) Institute for Liver and Digestive Health, Division of Medicine, University College London, United Kingdom; 2) Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 3) Centre of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; 4) Institute for Bioengineering of Catalonia, Barcelona, Spain 1. Kerbert A et al. Sci. Adv. 2025;11(10):eado1648 2. Sriphoosanaphan S et al, EASL Congress 2024 Abbreviations: AA, amino acid; COX, Cytochrome C oxidase; DEG, differentially expressed gene; KO, knock-out; NP , normal protein; OP , Ornithine Phenylacetate; TAK242, toll-like receptor 4 inhibitor; TLR4KO, TLR4 knock-out; WT , wild-type Hyperammonemia significantly impacted the OXPHOS complex IV and urea cycle. TLR4 plays an important role in mediating metabolic and mitochondrial dysfunction induced by hyperammonemia. The shared and distinct gene expression changes observed with TAK-242 and OP treatments highlight complementary mechanisms, which could be leveraged for more effective therapeutic strategies. * Genes with significant adjusted p-value are highlighted. DEG pattern for WT-AA vs. WT-NP DEG pattern for TLR4KO-AA vs. WT-AA DEG pattern for WT-TAK242 vs. WT-AA DEG pattern for WT-OP vs. WT-AA Cox7a1 (FC -0.76, p = 0.029) Cox6b2 (FC -1.64, p = 0.031) Glul (FC 1.49, p < 0.001) Glul (FC 1.51, p < 0.001) Oscp1 (FC -1.91, p = 0.022) Cox6b2 (FC -2.44, p = 0.002) Glul (FC 1.46, p < 0.001) Oscp1 (FC -1.90, p = 0.011) Cox6b2 (FC -3.20, p < 0.001) Cox7a1 (FC -1.63, p < 0.001)

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