Network pharmacology identifies IL6 as an important hub and target of tibolone for drug repurposing in traumatic brain injury.

Traumatic brain injury (TBI) is characterized by a complex network of signals mediating inflammatory, proliferative and apoptotic processes during its acute and chronic phases. Current therapies mitigate damage and are mainly for palliative care and there are currently no effective therapies for secondary damage. This suggests a need to discover a compound with a greater spectrum of action that can control various pathological aspects of TBI. Here we used a network pharmacology approach to explore the benefits of tibolone, an estrogen and androgen receptor agonist with broader actions in cells, as a possible repurposing drug for TBI therapy. Using different databases we retrieved the targets significantly associated to TBI and tibolone, obtaining 2700 and 652, respectively. The top 10 GO enriched terms were mostly related to cell proliferation, apoptosis and inflammation. Following protein-protein functional analysis, the top connected proteins were related to kinase activity (MAPK1/14/3, AKT1 PIK3R1), apoptosis (TP53, CASP3), growth factors (EGFR), estrogen signalling (ESR1) and inflammation (IL6, TNF), with IL6 as an important signalling hub belonging to the top GO categories. Thus, we identified IL6 as a cellular node which we then validated using molecular mechanics-generalized born surface area (MMGBSA) and docking to explore which tibolone metabolite might interact with this protein. Both 3α and 3β-OH tibolone seemed to bind better to IL6 at important sites responsible for its binding to IL6R. In conclusion, our study demonstrates key hubs involved in TBI pathology which indicates IL6 as a target molecule of tibolone as drug repurposing for TBI therapy.