Hibernating Bear Serum Triggers an Anti-fibrotic Signature in Human Fibroblasts, involving ECM Remodeling and MAPK Signaling Activation

Some hibernating species, such as the brown bear ( Ursus arctos ), can endure several months of physical inactivity and fasting without suffering the typical deterioration observed in inactive or starved non-hibernators, such as muscle atrophy, bone loss or systemic inflammation. The underlying physiological and molecular adaptive mechanisms may involve humoral factors circulating in the blood, which could help maintain cellular and tissue homeostasis under prolonged stress. To investigate the intracellular mechanisms triggered by blood components from hibernating bears, we treated human fibroblast cells with serum from either active bears, hibernating bears, or fetal bovine serum as controls. We then performed an untargeted proteomics analysis to identify changes in the treated cells. This revealed remodeling of extracellular matrix (ECM) and modulation of key regulatory pathways, indicating an anti-fibrotic signature in cells treated with hibernating bear serum. In particular, it was characterized by reduced levels of fibrotic markers such as collagens (COL2A1, COL11A1, COL9A1) and the TGF-β1-associated signaling component TGFBI, as well as activation of the MAPK cascade. Additionally, a decrease in the levels of inflammatory markers (IFI16, HMGB2, and HMGB), which play a key role in the fibrosis process, was observed. Overall, our study provides new evidence that hibernation-related circulating factors are associated with changes in pro-fibrosis pathways and ECM homeostasis in human cells. These findings suggest that hibernating bear serum may serve as a valuable model to explore mechanisms underlying anti-fibrotic gene expression programs and to identify potential targets for tissue preservation.