Interleukin-27 is a multitarget regulator of fibroblast remodeling in thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) is characterized by inflammation and tissue remodeling, including fibrosis and adipogenesis. Here, we identify interleukin-27 (IL-27) as a negative feedback immunomodulator in TAO. Serum IL-27α levels were significantly elevated in patients with TAO compared with healthy and inflammatory disease controls. In orbital fibroblasts (OFs), exogenous IL-27 suppressed IL-1β-induced proinflammatory cytokines and reduced hypoxia-induced NLRP3 inflammasome activation. IL-27 also attenuated TGF-β-driven fibrosis via p38 MAPK signaling in CD90⁺ OFs. Furthermore, in CD90^- OFs, IL-27 restrained adipogenic differentiation by dampening AKT signaling and suppressing hypoxia-induced adipogenesis in a ROS-dependent manner. Our results indicate that IL-27 signaling acts as a multifunctional regulator and negative feedback modulator that helps limit the pathological progression of TAO.