FGF2 Recalibrates Fibrotic Responses by Inhibiting TGF-β, Promoting Regenerative Repair

Tissue injury often leads to fibrotic scarring, a pathological outcome where functional tissue is replaced by non-functional scar tissue, rather than regenerative repair. This process is driven by complex signaling networks, with transforming growth factor-β (TGF-β) being a dominant promoter of extracellular matrix deposition and fibrosis. Current therapeutic strategies for chronic wounds and fibrotic disorders often fall short in achieving true regeneration, highlighting a critical need for interventions that can rebalance the healing trajectory. Fibroblast growth factor-2 (FGF2) has been identified as a crucial regulator with the potential to shift this balance towards functional restoration.

This review synthesized current mechanistic insights into FGF2 signaling, elucidating its regulatory interplay with TGF-β that favors regenerative repair over fibrosis. Researchers evaluated existing clinical trial evidence to assess the therapeutic potential of FGF2. The review also examined next-generation strategies designed to overcome translational barriers, including molecular engineering, chimeric growth factor design, and advanced stabilization approaches, aiming to enhance the clinical applicability of FGF2 for chronic wounds and fibrotic disorders.

The review highlights that FGF2 is a key modulator of repair outcomes, actively promoting inflammation resolution, proliferation, vascularization, and re-epithelialization. A central mechanism of its activity involves dynamic cross-talk with TGF-β, a primary driver of extracellular matrix deposition and fibrosis. Accumulating evidence, spanning both preclinical and clinical studies, consistently indicates that FGF2 inhibits TGF-β-mediated profibrotic signaling. This inhibition effectively shifts tissue remodeling towards regeneration rather than pathological scarring. Specifically, studies show that FGF2 accelerates wound closure and improves scar architecture. However, despite this compelling biological rationale, widespread clinical translation of FGF2 has been limited by rapid protein degradation and concerns regarding its proliferative signaling in oncogenic contexts. These limitations have constrained its incorporation into standard therapeutic strategies.

The core finding is that FGF2 actively inhibits TGF-β-mediated profibrotic signaling, thereby recalibrating tissue remodeling towards regenerative repair.