FGF2 Mediated USP42-PPAR Axis Activation Ameliorates Liver Oxidative Damage and Promotes Regeneration

Liver regeneration is critical for maintaining whole-body homeostasis, especially under the exposure to deadly chemical toxins. Understanding the molecular mechanisms underlying liver repair is critical for the development of intervention strategies to treat liver diseases. In this study, we identified ubiquitin-specific Proteases 42 (USP42) as a novel deubiquitinases (DUB) of peroxisome proliferators-activated receptor γ (PPARγ) in hepatocytes. This DUB interacted, deubiquitinated and stabilized PPARγ, and increased PPAR targeted proliferative and anti-oxidative gene expressions, which protects liver from carbon tetrachloride (CCL4) induced oxidative injury and promotes liver regeneration. In addition, fibroblast growth factor 2 (FGF2) initiated USP42 expression and enhanced the interaction between USP42 and PPARduring liver regeneration process. Moreover, the PPARfull agonist, rosiglitazone (RSG), possesses the ability to further reinforce the USP42-PPARinterplay, which enlightens us to construct an extracellular vesicle-based targeting strategy to activate liver USP42-PPAR axis and promote liver regeneration. In summary, our work uncovers the importance of USP42-PPAR axis mediated liver tissue homeostasis, and provides a promising regimen to target this protein-protein interplay for liver regeneration.