DPP4 is a serine protease with multifaceted roles extending beyond its catalytic activity. Enzymatically, DPP4 cleaves dipeptides from substrates and functions as a signaling receptor, including serving as a receptor for MERS-CoV-2 1. In skin biology, DPP4 marks a major fibroblast population (SFRP2+) involved in matrix deposition and inflammatory processes 1. DPP4's pathological significance spans multiple diseases. In rheumatoid arthritis, DPP4 undergoes ubiquitin-dependent degradation by the E3 ligase Mid1; DPP4 loss paradoxically promotes synovial cell proliferation and inflammation, suggesting DPP4 normally restrains synovial activation 2. In hypertrophic scarring, DPP4 promotes TGFβ1-mediated myofibroblast differentiation and extracellular matrix overproduction; DPP4 inhibition reduces fibrosis 3. In osteoarthritis, DPP4 exacerbates progression through enzyme-independent mechanisms by promoting mitochondrial dysfunction and chondrocyte senescence via interaction with MYH9 4. In hepatocellular carcinoma, DPP4 upregulation by ketogenic metabolites enhances ferroptosis susceptibility 5. In aortic valve calcification, DPP4 stabilization through reduced ubiquitination promotes osteogenic differentiation 6. In lung cancer, DPP4 drives metabolic reprogramming of drug-tolerant persisters through fatty acid oxidation and antioxidant pathways 7. DPP4 genetic variants associate with drug-induced bullous pemphigoid risk in diabetic patients 8. These findings position DPP4 as a multifunctional therapeutic target across inflammatory, fibrotic, and malignant diseases.