Silk Fibroin Counteracts Fibroblast Senescence to Restore ECM Homeostasis in Aged Skin.

Skin aging is characterized by a progressive decline in regenerative capacity, primarily driven by fibroblast senescence, oxidative stress, chronic inflammation, and the degradation of type I/III collagen, culminating in an extracellular matrix (ECM) imbalance. Current injectable fillers-such as hyaluronic acid, collagen, and PLLA-provide temporary structural support but fail to address the underlying cellular senescence or restore ECM homeostasis, highlighting the need for regenerative biomaterials. Silk fibroin (SF), a natural protein, self-assembles into a β-sheet-rich scaffold that structurally supports fibroblasts in depositing collagen and elastin, thereby improving the skin's ECM, accelerating wound healing, and promoting tissue regeneration. However, its role in modulating fibroblast senescence and ECM remodeling remains unclear. This study demonstrates that SF provides a suitable microenvironment for the adhesion and proliferation of fibroblasts, reducing the accumulation of SASP factors and facilitating the transition of fibroblasts from a senescent to a functional state. Furthermore, SF improves the skin microenvironment by reducing reactive oxygen species (ROS) and matrix metalloproteinase (MMP) expression through modulation of the ROS-MAPK-AP-1-MMP signal pathway, thereby delaying collagen degradation in aged skin. These findings reveal that SF uniquely rejuvenates fibroblasts and restores ECM homeostasis through a non-inflammatory mechanism, distinguishing it from conventional fillers that rely on inflammatory pathways for collagen induction. This work establishes SF as a next-generation injectable biomaterial with dual targeting of cellular senescence and ECM imbalance, offering a transformative strategy for regenerative dermatology and personalized anti-aging approaches.