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Farnesol Targets the GSTP1/MAPK Axis to Inhibit Trauma-Induced Tendon Heterotopic Ossification

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE317543 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Background: The tendon-bone interface (TBI) frequently proves refractory to restoration following surgical reconstruction or even surgical failure, due to the intricate nature of its structure. α-Asarone (αASA), an active ingredient derived from the traditional Chinese medicinal plant Calamus, has been demonstrated to possess beneficial effects in the treatment of inflammatory and osteoporotic conditions. However, its impact on TBI has yet to be investigated. Objective: This study aimed to elucidate the therapeutic effects of αASA on TBI in vivo and in vitro, gain insight into the underlying mechanisms involved, and assess its potential medicinal value in humans. Methods: A mouse model and a cellular model of tendon-bone interface (TBI) healing were developed. The impact of αASA on TBI was investigated at both the in vitro and vivo levels through a range of techniques, including protein gene assays, cell staining, biomechanics, imaging, and histology. Concurrently, network pharmacology, transcriptomics, molecular docking, transcription factor prediction, and experimental validation were employed to conduct a comprehensive investigation of its specific effects and mechanism of action. Subsequently, In addition, the clinical medicinal value of αASA was validated by human BMSCs (hBMSCs). Results: In vivo, αASA treatment enhanced the biomechanical properties and osseointegration of tendon-bone samples in mice. In vitro, αASA promoted osteogenic differentiation of BMSCs, as evidenced by staining and the expression of osteogenic marker genes. Using network pharmacology, we identified 29 core co-target genes of αASA in the treatment of TBI. The top 20 differentially expressed genes (DEGs) underwent GO, KEGG, and GSEA enrichment analyses, revealing their involvement in tissue mineralization and ossification processes. Additionally, 207 transcription factors (TFs) were predicted for these DEGs, with 9 identified as core co-target genes. Surface plasmon resonance (SPR) confirmed the strong affinity of αASA for the transcription factor PPARG, while luciferase assays demonstrated PPARG binding to the Dmp1 promoter to regulate transcription. αASA also enhanced osteogenic differentiation in human BMSCs, supporting its potential for clinical application. Conclusion: αASA promotes osteogenic differentiation and improves TBI healing in mBMSCs by targeting and down-regulating the transcription factor PPARG to inhibit its binding to the Dmp1 promoter, while exerting the same effect in hBMSCs.

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Farnesol Targets the GSTP1/MAPK Axis to Inhibit Trauma-Induced Tendon Heterotopic Ossification

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