FGF2 in the regulation of regenerative repair and fibrosis: TGF-β cross-talk and therapeutic advances

Regenerative repair following tissue injury depends on tightly coordinated signaling networks that determine whether healing culminates in functional restoration or fibrotic scarring. Among these regulators, fibroblast growth factor-2 (FGF2) has emerged as a key modulator of repair outcomes. Mechanistically, FGF2 promotes inflammation resolution, proliferation, vascularization, and re-epithelialization. A central feature of its activity is dynamic cross-talk with transforming growth factor-β (TGF-β), a dominant driver of extracellular matrix deposition and fibrosis. Accumulating evidence indicates that FGF2 inhibits TGF-β-mediated profibrotic signaling, thereby shifting tissue remodeling toward regeneration rather than pathological outcomes. This interaction is supported by both preclinical and clinical evidence showing that FGF2 accelerates wound closure and improves scar architecture. However, despite the compelling biological rationale, the widespread clinical translation of FGF2 has been limited by rapid protein degradation and concerns about proliferative signaling in oncogenic contexts. These limitations have constrained its incorporation into standard therapeutic strategies for chronic wounds and fibrotic disorders. This review provides a synthesis of current mechanistic insights into FGF2 signaling and elucidates its regulatory interplay with TGF-β that favors regenerative repair over fibrosis. We evaluated clinical trial evidence and examined next-generation strategies to overcome translational barriers, including molecular engineering, chimeric growth factor design, and advanced stabilization approaches. By clarifying the regulatory role of FGF2 in the repair trajectory, we highlight its potential to recalibrate fibrotic responses and improve regenerative outcomes.