Shih_2026_Front.Endocrinol.(Lausanne)_17_1883214

Graves' orbitopathy (GO) is characterized by inflammation, hyaluronan accumulation, tissue expansion, and fibrosis of orbital tissues, while effective antifibrotic medical therapies remain limited. Dipeptidyl peptidase-4 inhibitors (DPP4i), widely used for type 2 diabetes, have been reported to modulate fibroblast activity and fibrotic responses in several organs. This study investigated the effects of DPP4i on primary human orbital fibroblasts and explored their potential relevance to GO. Orbital fibroblasts were obtained from patients with GO and non-GO controls. DPP4 protein expression was assessed by Western blotting. The effects of linagliptin and sitagliptin on fibroblast proliferation, myofibroblastic differentiation, adipogenesis, and hyaluronan production were evaluated using DAPI nuclei counts, alpha-smooth muscle actin (alpha-SMA) immunofluorescence and Western blotting, Oil Red O staining, and ELISA, respectively. DPP4 protein was detected in orbital fibroblasts from both GO and non-GO groups. Linagliptin and sitagliptin significantly reduced transforming growth factor-beta (TGF-beta)-induced alpha-SMA expression in GO fibroblasts, whereas their effects in non-GO fibroblasts were modest. Both linagliptin and sitagliptin significantly suppressed interleukin-1beta (IL-1beta)-stimulated hyaluronan production in GO and non-GO fibroblasts. Neither inhibitor significantly altered DAPI-based cell number measurements or lipid accumulation in either group. These findings provide in vitro evidence that DPP4i modulate selected orbital fibroblast phenotypes related to myofibroblastic differentiation and cytokine-induced hyaluronan production. Further mechanistic, pharmacokinetic, in vivo, and clinical studies are warranted to clarify their relevance to GO-related tissue remodeling.