The present invention is based, in part, on our studies of molecular pathways that include the deubiquitinase CYLD. Accordingly, the present invention features, inter alia, nucleic acid constructs that express CYLD or a biologically active variant thereof (e.g., a variant including the catalytic domain), nucleic acids that inhibit the expression of a negative regulator of CYLD (e.g., PDE4B or LNK2), nucleic acids that modulate the expression of downstream CYLD targets (e.g., Akt, by inhibiting or promoting the expression of the downstream target), compositions including one or more of these types of constructs (e.g., pharmaceutical compositions), kits including one or more of the compositions described herein and instructions for use, screening methods to identify therapeutic agents {e.g., anti-inflammatory agents) that upregulate CYLD, downregulate a negative regulatory of CYLD, or modulate (e.g., inhibit) a downstream CYLD target (e.g., Akt), and various methods of treatment including the administration of the nucleic acids described above, protein biotherapeutics, and/or small molecules, alone or in combination, to address cancer, inflammation, and fibrosis. The compositions described herein can be used in the preparation of a medicament (e.g., used in the preparation of a medicament to treat cancer, inflammation, fibrosis, or one or more of the more specific conditions described herein).

Methods of lowering blood glucose and treating Type 2 diabetes in a subject by increasing expression or activity of phosphodiesterase 4D isoform 3 (PDE4D3) in adipocytes of the subject are described. In some instances, expression of PDE4D3 in adipocytes is increased by administering a vector that expresses PDE4D3 specifically in adipocytes, or via gene editing by introduction of a PDE4D3-encoding nucleic acid into adipocytes. Use of small molecule activators of PDE4D3 that are targeted to adipocytes is also described.