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.