Drug repurposing in MASLD and MASH-cirrhosis: targets and treatment approaches based on pathways analysis.

SILVIA SOOKOIAN; CARLOS JOSE PIROLA

Clinical Application of Repurposed Drugs

Academic Press

Lugar: Londres; Año: 2024;

Rather than providing a classical literature review, this work is focused on understanding the complexity of NASH-cirrhosis. To achieve this, we used gene/protein and set enrichment analysis to predict druggable pathways for the treatment of this condition. We show that the pathogenesis of NASH-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 NASH 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 NASH-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 NASH may not necessarily be of choice for NASH 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.