Data Sheet 3_Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models.pdf

BackgroundOATD-01 is a chitinase-1 (CHIT1) inhibitor, reducing inflammation and fibrosis in animal models where chronic inflammation leads to tissue remodeling. CHIT1, predominantly secreted by macrophages, is overexpressed in metabolic dysfunction-associated steatohepatitis (MASH).
Methods and resultsIn the study, we demonstrated the therapeutic efficacy of OATD-01 in two murine models (STAM, DIAMOND) and one rat model (CDHFD) of MASH. RNA-Seq analysis of livers obtained from CDHFD rat model revealed that OATD-01 reversed MASH-dysregulated genes. In addition to reducing inflammation and fibrosis observed in the rat model, RNA-Seq demonstrated that OATD-01 regulated key metabolic processes such as acetyl-CoA metabolism, triglyceride metabolism, cholesterol synthesis, cholesterol flux, and glycolysis. Using functional assay performed on bone marrow-derived macrophages (BMDMs) we demonstrated that both genetic and pharmacological inactivation of CHIT1 resulted in inhibition of glucose uptake. As a consequence, our data suggest decreased glycolysis, accompanied by increased ATP levels, lower citrate, and increased acetate levels, ultimately leading to a reduced IL-1β secretion in BMDMs.
ConclusionsThese results revealed the key role for CHIT1 in regulating metabolism. OATD-01 is a macrophage modulator that can directly restore metabolic balance and consequently inhibit inflammation and fibrosis, supporting its use for MASH treatment.

背景
OATD-01是几丁质酶-1（chitinase-1, CHIT1）抑制剂，可在慢性炎症引发组织重塑的动物模型中减轻炎症与纤维化。几丁质酶-1主要由巨噬细胞分泌，在代谢功能障碍相关脂肪性肝炎（metabolic dysfunction-associated steatohepatitis, MASH）中呈过表达状态。

方法与结果
本研究在两种小鼠MASH模型（STAM、DIAMOND）及一种大鼠MASH模型（CDHFD）中验证了OATD-01的治疗功效。对CDHFD大鼠模型的肝脏开展RNA测序（RNA-Seq）分析后发现，OATD-01可逆转MASH诱导的基因表达失调。除减轻该大鼠模型中的炎症与纤维化外，RNA测序结果还显示OATD-01能够调控多项关键代谢过程，包括乙酰辅酶A代谢、甘油三酯代谢、胆固醇合成、胆固醇通量以及糖酵解。通过对骨髓来源巨噬细胞（bone marrow-derived macrophages, BMDMs）开展功能实验，本研究证实：对CHIT1进行遗传与药理学双通路失活，均可抑制葡萄糖摄取。据此，本研究数据表明，糖酵解水平降低伴随ATP水平升高、柠檬酸含量降低及乙酸盐含量升高，最终使骨髓来源巨噬细胞中的IL-1β分泌量减少。

结论
上述结果揭示了CHIT1在代谢调控中的关键作用。OATD-01作为一种巨噬细胞调节剂，可直接恢复代谢平衡，进而抑制炎症与纤维化，为其用于代谢功能障碍相关脂肪性肝炎的治疗提供了支持。