Farnesol Targets the GSTP1/MAPK Axis to Inhibit Trauma-Induced Tendon Heterotopic Ossification
Background: Heterotopic ossification (HO), characterized by pathological bone formation in extra-skeletal tissues such as tendon, often results in debilitating tissue dysfunction. HO of tendons primarily arises from abnormal osteogenic differentiation of tendon stem cells following injury. Despite being a common clinical occurrence, the cellular and molecular mechanisms of tendon HO are poorly understood, and effective treatments remain elusive. Farnesol, a natural isoprenoid alcohol abundant in citrus fruits, lavender, and royal jelly, is known for its potent anti-inflammatory, antioxidant, and antitumor properties. However, its applications in tissue engineering are rarely explored, particularly in musculoskeletal repair. Here, we provide the first report on the therapeutic potential of Farnesol in attenuating tendon HO and elucidate the associated molecular mechanisms.Methods: This study evaluated the effects of Farnesol on osteogenic differentiation of tendon-derived stem cells using both in vitro and in vivo models. The molecular mechanisms underlying the therapeutic effects of Farnesol on tendon HO were revealed by RNA sequencing combined with network pharmacology analysis, identifying the GSTP1/MAPK axis as a potential target pathway. In vitro rescue experiments using a specific GSTP1 inhibitor were conducted to confirm whether Farnesol primarily exerted its therapeutic effects through GSTP1.Results: The results demonstrated significant effects of Farnesol on attenuating tendon HO both in vitro and in vivo. Combined analysis of transcriptomics and network pharmacology indicated that Farnesol functions by targeting the GSTP1/MAPK signaling axis. These findings were further validated by in vitro experiments using the GSTP1 inhibitor, which reversed the suppressive effects of Farnesol on osteogenesis.Conclusion: Farnesol inhibits the progression of post-traumatic tendon HO by targeting the GSTP1/MAPK pathway. These findings provide new insights into the potential of using Farnesol as a therapeutic agent for HO. Overall design: RNA sequencing analysis was performed on the control group and farnesol-treated group of rat TDSCs on the third day of osteogenic differentiation.