Dysregulated adipokine production is an influencing factor for the homeostatic imbalance of tendons. High levels of serum leptin may be a potential link between increasing adiposity and tendinopathy, while the detailed mechanistic explanation was not well-defined. In this study, we investigated the regulatory role of leptin in the tendon stem/progenitor cells (TSPCs) and the molecular mechanism within, and determined the effect of high levels of leptin on tendon recovery. We demonstrated that leptin reduced the viability of isolated rat TSPCs in a dose-dependent way, accompanied with increased transdifferentiation and altered gene expression of a series of extracellular matrix (ECM) enzymatic modulators. Also, we found that leptin could dose-dependently promote TSPCs senescence, while exhibiting limited effect in apoptotic or autophagic induction. Mechanistic study evidenced that leptin treatment increased the AKT/mTOR signaling activity and elevated the expression of leptin receptor (LEPR) in TSPCs, without marked change in MAPK or STAT5 activation. Further, we confirmed that rapamycin treatment, but not AKT inhibition, effectively reduced the leptin-promoted TSPCs senescence. In a rat model with Achilles wounding, exposure to leptin profoundly delayed tendon healing, which was effectively rescued with rapamycin treatment. Our results suggested that leptin could cause intrinsic cellular deficits in TSPCs and impede tendon repair through the AKT/mTOR signaling pathway. These findings evidenced for an important role of elevated leptin levels in the care of tendinopathy and tendon tears., Competing Interests: Declaration of Competing Interest ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Changbin Lei reports article publishing charges and equipment, drugs, or supplies were provided by Department of Science and Technology of Hunan Province. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)