Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease that can progress to fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately death, but there are no approved therapies. Leukotriene B4 (LTB4) is a potent pro-inflammatory chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high-affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased hepatic steatosis. To validate the therapeutic efficacy of BLT1 inhibition in an inflammatory and pro-fibrotic mouse model of MASH and fibrosis, mice were challenged with a choline-deficient, l-amino acid-defined, high-fat diet and treated with a BLT1 antagonist at 30 or 90 mg/kg for 8 weeks. Liver function, histology, and gene expression were evaluated at the end of the study. Treatment with the BLT1 antagonist significantly reduced plasma lipids and liver steatosis but had no impact on liver injury biomarkers or histological endpoints such as inflammation, ballooning, or fibrosis compared to control. Artificial intelligence-powered digital pathology analysis revealed a significant reduction in steatosis co-localized fibrosis in livers treated with the BLT1 antagonist. Liver RNA-seq and pathway analyses revealed significant changes in fatty acid, arachidonic acid, and eicosanoid metabolic pathways with BLT1 antagonist treatment; however, these changes were not sufficient to impact inflammation and fibrosis endpoints. Targeting this LTB4–BLT1 axis with a small molecule inhibitor in animal models of chronic liver disease should be considered with caution, and additional studies are warranted to understand the mechanistic nuances of BLT1 inhibition in the context of MASH and liver fibrosis.

中文翻译：

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白三烯 B4 受体 1 不介导小鼠肝纤维化模型的疾病进展

代谢功能障碍相关脂肪性肝炎 (MASH) 是一种常见的肝脏疾病，可进展为纤维化、肝硬化、肝细胞癌并最终导致死亡，但尚无批准的治疗方法。白三烯 B4 (LTB4) 是一种有效的促炎化学引诱剂，可驱动巨噬细胞和中性粒细胞趋化性，其高亲和力受体白三烯 B4 受体 1 (BLT1) 的遗传缺失或抑制可改善胰岛素敏感性并减少肝脏脂肪变性。为了验证 BLT1 抑制在 MASH 和纤维化炎症和促纤维化小鼠模型中的治疗效果，用缺乏胆碱、L-氨基酸限定的高脂肪饮食对小鼠进行挑战，并在 30 ℃时用 BLT1 拮抗剂治疗。或 90 毫克/公斤，持续 8 周。在研究结束时评估肝功能、组织学和基因表达。与对照组相比，BLT1拮抗剂治疗显着降低了血浆脂质和肝脏脂肪变性，但对肝损伤生物标志物或组织学终点（例如炎症、气球样变或纤维化）没有影响。人工智能驱动的数字病理学分析显示，用 BLT1 拮抗剂治疗的肝脏中脂肪变性共定位纤维化显着减少。肝脏 RNA-seq 和通路分析揭示了 BLT1 拮抗剂治疗后脂肪酸、花生四烯酸和类二十烷酸代谢通路的显着变化；然而，这些变化不足以影响炎症和纤维化终点。在慢性肝病动物模型中使用小分子抑制剂靶向 LTB4-BLT1 轴应谨慎考虑，并且需要进行更多研究来了解 MASH 和肝纤维化背景下 BLT1 抑制的机制细微差别。