Pharmacological Inhibition of STING with H-151 Promotes Rotator Cuff Healing in Aged Rats

Background: Although the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway is a key driver of inflammaging in age-related musculoskeletal disorders, its role in age-related rotator cuff tears (RCTs) remains unknown. This study investigated whether inhibition of the cGAS-STING pathway with H-151 could improve tendon-to-bone healing in aged rats after rotator cuff repair (RCR). Methods: Forty-eight Sprague-Dawley rats were assigned to 4 groups: young control (sham surgery), aged control (sham surgery), aged RCT (RCR with fibrin), and aged RCT+H-151 (RCR with H-151-loaded fibrin). Rats in the RCT groups underwent bilateral RCR, after which the tendon-bone enthesis was treated with the respective fibrin gel. The status of the cGAS-STING pathway, expression of inflammaging and differentiation markers, and histological and biomechanical properties of the supraspinatus-humerus complex were evaluated. Results: The cGAS-STING pathway was markedly activated at the tendon-bone enthesis in the aged rats. Treatment with H-151 effectively suppressed its downstream effectors ( Ifnb and Cxcl10 ), reduced inflammaging markers ( Cdkn2a, Cdkn1a, Il1b, and Il6 ), and enhanced the expression of chondrogenic ( Acan and Col2a1 ) and tenogenic ( Tnmd and Scx ) differentiation markers. Histological assessment revealed improved collagen organization and enhanced cartilage regeneration at the enthesis in the aged RCT+H-151 group, which also achieved a higher histological score. Biomechanically, the aged RCT+H-151 group exhibited significantly increased failure load, stiffness, and tensile stress compared with the aged RCT group. Conclusions: The cGAS-STING pathway was activated at the tendon-bone enthesis in aged rats. The inhibition of STING with H-151 in similar rats attenuated inflammaging, promoted collagen maturation and fibrocartilage regeneration, and substantially improved the biomechanical properties of the repaired enthesis. Clinical Relevance: Inhibition of the cGAS-STING pathway using STING antagonists may be a promising therapeutic strategy for enhancing rotator cuff healing in older patients.