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

Heterotopic ossification (HO) within tendons leads to debilitating tissue dysfunction, primarily arising from the abnormal osteogenic differentiation of tendon-derived stem cells (TDSCs). Despite its clinical prevalence, effective pharmacological treatments remain elusive. Farnesol, a natural isoprenoid with potent anti-inflammatory properties, represents a novel but unexplored candidate for musculoskeletal repair. This study aimed to evaluate the therapeutic efficacy of Farnesol in attenuating tendon HO and to elucidate the specific molecular mechanisms driving its effects. The anti-osteogenic effects of Farnesol were assessed using in vitro TDSC differentiation assays and an in vivo tendon injury model. Integrated RNA sequencing and network pharmacology analysis were employed to identify potential molecular targets. The mechanism was rigorously validated through rescue experiments using a specific GSTP1 inhibitor. Farnesol treatment significantly inhibited osteogenic differentiation in vitro and attenuated ectopic bone formation in vivo. Mechanistic screening identified the GSTP1/MAPK signaling axis as a critical regulatory pathway. Crucially, the administration of a GSTP1 inhibitor reversed the suppressive effects of Farnesol on osteogenesis, confirming GSTP1 as the primary mediator. Farnesol effectively inhibits the progression of post-traumatic tendon HO by targeting the GSTP1/MAPK pathway. These findings provide the first evidence of Farnesol's therapeutic potential in preventing pathological ossification.