胆碱缺乏型L-氨基酸高脂饮食（CDAA-HFD）小鼠模型广泛用于临床前代谢功能障碍相关脂肪性肝炎（MASH）研究。为了验证 CDAA-HFD 小鼠，我们评估了疾病进展以及对索马鲁肽、lanifibranor、elafibranor、奥贝胆酸 (OCA)、firsocostat 和 resmetirom 饮食和药物干预的反应。在喂食 CDAA-HFD 的 C57BL/6J 小鼠中进行了疾病表型分析3-20 周，并使用 MASLD 人类邻近度评分 (MHPS) 进行排名。索马鲁肽、lanifibranor、elafibranor、OCA、firsocostat 或 resmetirom 被描述为为期 8 周的治疗干预，在 CDAA-HFD 喂养 6 周后开始。在 CDAA-HFD 饮食喂养后 3 周开始，索马鲁肽和拉尼夫拉诺作为早期（预防性）治疗进行了为期 9 周的进一步评估。此外，在 CDAA-HFD 喂养 6 周后，还描述了 8 周饮食干预（饮食逆转）的益处。 CDAA-HFD 小鼠表现出非肥胖表型，MASH 和纤维化快速发生和进展，与人类 MASH 纤维化高度相似，并且在饮食诱导 20 周后出现肿瘤。当作为预防而非治疗干预时，索马鲁肽和拉尼布诺可部分逆转纤维化。 Elafibranor是唯一改善纤维化的介入药物。相比之下，CDAA-HFD 小鼠的食物逆转导致脂肪变性完全消退，肝脏炎症和纤维化得到改善。 CDAA-HFD 小鼠重现了晚期 MASH 的组织学特征，伴有进行性严重纤维化，但不存在临床转化性肥胖代谢障碍表型。 CDAA-HFD 小鼠适合分析直接针对肝脏脂质代谢、炎症和纤维化的候选药物。药物干预的时机对于确定模型中的抗纤维化药物疗效至关重要。

The choline-deficient L-amino acid defined-high fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat and resmetirom.Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 weeks and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat or resmetirom were profiled as treatment intervention for 8 weeks, starting after 6 weeks of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 weeks, starting 3 weeks after CDAA-HFD diet feeding. Additionally, benefits of dietary intervention (chow reversal) for 8 weeks were characterized following 6 weeks of CDAA-HFD feeding. CDAA-HFD mice demonstrated a non-obese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 weeks of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention, but not as treatment intervention. Elafibranor was the only interventional drug to improve fibrosis. In comparison, chow-reversal resulted in complete steatosis regression with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model.