FGF2 Mediated USP42‐PPARγ Axis Activation Ameliorates Liver Oxidative Damage and Promotes Regeneration

Abstract Liver regeneration is critical for maintaining whole‐body homeostasis, especially under 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, ubiquitin‐specific Proteases 42 (USP42) is identified as a novel deubiquitinases (DUB) of peroxisome proliferators‐activated receptor γ (PPARγ) in hepatocytes. This DUB interacted, deubiquitinated, and stabilized PPARγ, and increased PPARγ targeted proliferative and antioxidative gene expressions, which protects the 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 PPARγ during the liver regeneration process. Moreover, the PPARγ full agonist, rosiglitazone (RSG), possesses the ability to further reinforce the USP42‐PPARγ interplay, which enlightens to construct of an extracellular vesicle‐based targeting strategy to activate the liver USP42‐PPARγ axis and promote liver regeneration. In summary, the work uncovers the importance of USP42‐PPARγ axis‐mediated liver tissue homeostasis and provides a promising regimen to target this protein‐protein interplay for liver regeneration.