CTCF protects against tendinopathy and transcriptionally activates Nrf2-dependent antioxidant signaling

Tendinopathy (TP) is a common degenerative musculoskeletal disorder characterized by extracellular matrix disorganization, chronic inflammation, and impaired tendon function. Oxidative stress has been recognized as a key contributor to tendon degeneration, yet the upstream regulatory mechanisms controlling antioxidant responses remain poorly understood. Here we identify the chromatin architectural protein CCCTC-binding factor (CTCF) as a critical regulator of tendon homeostasis. CTCF expression was significantly reduced in human tendinopathic tissues and in two murine models of tendinopathy, including collagenase-induced injury and treadmill overuse. Restoration of CTCF expression markedly alleviated tendon degeneration, improved collagen fiber organization, and suppressed inflammatory responses. Mechanistically, chromatin immunoprecipitation and luciferase reporter assays demonstrated that CTCF directly binds to the promoter of nuclear factor erythroid 2–related factor 2 (Nrf2) and promotes its transcription. Upregulation of CTCF enhanced Nrf2 expression and increased downstream antioxidant gene expression, including HO-1 and NQO1, thereby reducing intracellular reactive oxygen species accumulation in tenocytes. In vivo, Nrf2 deficiency aggravated tendon degeneration and abolished the protective effects of CTCF overexpression. Conversely, pharmacological activation of Nrf2 with sulforaphane significantly attenuated tendinopathy progression. Together, these findings reveal a previously unappreciated CTCF–Nrf2 regulatory axis that protects against oxidative stress–induced tendon degeneration and may represent a potential therapeutic target for tendinopathy.