Beyond local injury: pathogenic roles of metabolic, endocrine, and aging-associated systemic factors in tendinopathy and novel therapeutic strategies.

Tendinopathy, characterized by persistent pain and impaired function, is a globally prevalent condition imposing heavy socioeconomic burdens. Long regarded as an isolated local lesion, it is increasingly recognized as a regional manifestation of systemic dysregulation driven by the metabolic-endocrine-aging axis-not merely a peripheral "background factor." This review systematically analyzes four key pathogenic pathways: hyperglycemia-induced advanced glycation end-product (AGE) deposition, dyslipidemia-driven metabolic inflammation, sex hormone fluctuation-mediated collagen homeostasis disruption, and the cellular senescence-senescence-associated secretory phenotype (SASP) cascade. Together, these systemic factors remodel the tendon cell microenvironment, alter extracellular matrix biomechanics, and reduce the tissue's mechanical load tolerance. Traditional local-focused treatments have demonstrated limited efficacy, requiring a shift to a "systemic-local synergistic regulation" paradigm. Critically, a new clinical staging system integrating systemic risk factors is urgently needed. By establishing a "systemic-local" crosstalk model and highlighting the urgent need for a novel clinical staging system integrating systemic risk factors-our primary novel contribution-this review provides key insights for researchers and clinicians, supporting the optimization of personalized therapeutic strategies and improved clinical outcomes for tendinopathy.