Role of statins in regulating molecular pathways following traumatic brain injury: A system pharmacology study

Traumatic brain injury (TBI) is a serious disorder with debilitating physical and psychological complications. Previous studies have indicated that genetic factors have a critical role in modulating the secondary phase of injury in TBI. Statins have interesting pleiotropic properties such as antiapoptotic, antioxidative, and anti-inflammatory effects, which make them a suitable class of drugs for repurposing in TBI. In this study, we aimed to explore how statins modulate proteins and pathways involved in TBI using system pharmacology. We first explored the target associations with statins in two databases to discover critical clustering groups, candidate hub and critical hub genes in the network of TBI, and the possible connections of statins with TBI-related genes. Our results showed 1763 genes associated with TBI. Subsequently, the analysis of centralities in the PPI network displayed 55 candidate hub genes and 15 hub genes. Besides, MCODE analysis based on threshold score:10 determined four modular clusters. Intersection analysis of genes related to TBI and statins demonstrated 204 shared proteins, which suggested that statins influence 31 candidate hub and 9 hub genes. Moreover, statins had the highest interaction with MCODE1. The biological processes of the 31 shared proteins are related to gene expression, inflammation, antioxidant activity, and cell proliferation. Biological enriched pathways showed Programmed Cell Death proteins, AGE-RAGE signaling pathway, C-type lectin receptor signalling pathway, and MAPK signaling pathway as top clusters. In conclusion, statins could target several critical post-TBI genes mainly involved in inflammation and apoptosis, supporting the previous research results as a potential therapeutic agent.