Metabolic-pathway-based classification of tendinopathy reveals a precise therapeutic strategy targeting chondro-modulatory tenocytes.

Tendinopathy is a prevalent degenerative condition driven by complex metabolic dysregulation, yet its inherent metabolic heterogeneity remains poorly characterized, hindering targeted therapeutic development. To address this, we performed systematic multi-omics profiling of human rotator cuff tendinopathy (n = 192). Unsupervised clustering based on the activity of 149 metabolic pathways, validated by pseudotargeted metabolomics, revealed three distinct metabolic-pathway-based classifications (MPCs): MPC-G (glycolytic), with upregulated carbohydrate and glycan metabolism; MPC-F (fatty acid oxidative), exhibiting elevated fatty acid oxidation and amino acid metabolism; and MPC-I (imbalanced), showing dysregulated metabolite homeostasis alongside moderate glycolysis increase and fatty acid oxidation decrease. Single-cell RNA sequencing identified classification-specific pathogenic cell populations. Mechanistically, hypoxia-induced glycolytic reprogramming via HIF-1α led to lactate accumulation, which in turn stabilized HIF-1α, forming a feed-forward loop that promoted the formation of chondro-modulatory tenocytes and drove MPC-G pathogenesis. Genetic inhibition of HIF-1α and direct targeting of lactate both attenuated disease progression, validating the critical role of this axis. Notably, we identified and validated the clinical drug temsirolimus as an effective agent specifically against MPC-G in experimental models. Collectively, our study delineates the metabolic heterogeneity of tendinopathy and establishes a classification framework that enables precision medicine strategies tailored to distinct metabolic profiles.