设计和预测新的药物靶标以加速治疗代谢功能障碍相关脂肪性肝炎(MASH)肝硬化的药物发现是一项具有挑战性的任务。存在叠加(嵌套)和共同发生的临床和组织学表型,即MASH和肝硬化,可以部分解释这一点。因此,在这种情况下,每个子表型都有自己的一套病理生理机制,触发器,和过程。这里,我们使用基因/蛋白质和集合富集分析来预测MASH肝硬化治疗的药物途径。我们的发现表明,MASH肝硬化的发病机理可以通过多种扰动来解释,同时,和重叠的分子过程。在这种情况下,每个子表型都有自己的一套病理生理机制,触发器,和过程。因此,我们使用系统生物学建模来提供证据,证明MASH和肝硬化矛盾地呈现独特和独特以及常见的疾病机制,包括分子靶标的网络。更重要的是,途径分析揭示了与免疫反应调节一致的简单结果,细胞周期控制,和表观遗传调控。总之,选择MASH肝硬化的潜在治疗方法应通过更好地了解潜在的生物学过程和逐渐损害肝组织及其潜在结构的分子扰动来指导。MASH患者的治疗选择可能不一定是MASH肝硬化的选择。因此,疾病的生物学和与其自然史相关的过程必须处于决策过程的最前沿。
Designing and predicting novel drug targets to accelerate drug discovery for treating metabolic dysfunction-associated steatohepatitis (MASH)-
cirrhosis is a challenging task. The presence of superimposed (nested) and co-occurring clinical and histological phenotypes, namely MASH and
cirrhosis, may partly explain this. Thus, in this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Here, we used gene/protein and set enrichment analysis to predict druggable pathways for the treatment of MASH-cirrhosis. Our findings indicate that the pathogenesis of MASH-
cirrhosis can be explained by perturbations in multiple, simultaneous, and overlapping molecular processes. In this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Therefore, we used systems biology modeling to provide evidence that MASH and
cirrhosis paradoxically present unique and distinct as well as common disease mechanisms, including a network of molecular targets. More importantly, pathway analysis revealed straightforward results consistent with modulation of the immune response, cell cycle control, and epigenetic regulation. In conclusion, the selection of potential therapies for MASH-cirrhosis should be guided by a better understanding of the underlying biological processes and molecular perturbations that progressively damage liver tissue and its underlying structure. Therapeutic options for patients with MASH may not necessarily be of choice for MASH
cirrhosis. Therefore, the biology of the disease and the processes associated with its natural history must be at the forefront of the decision-making process.