Fibrotic Mechanisms and Therapeutic Strategies in Skin Disorders

Fibrosis in the skin arises from a dysregulated wound-healing cascade in which persistent activation of dermal fibroblasts and excessive deposition of extracellular matrix proteins, notably type I and III collagen, lead to tissue stiffening and scarring. Central to this process is transforming growth factor-β (TGF-β) signalling, which drives myofibroblast differentiation, Smad2/3 phosphorylation and transcription of pro-fibrotic genes. Mechanical stress, reactive oxygen species and chronic inflammation further amplify fibroblast activity and promote a feed-forward loop of collagen synthesis. Keratinocytes, immune cells and endothelial cells all contribute paracrine factors that modulate fibroblast behaviour. Therapeutic strategies under investigation target key nodes in this network: small-molecule inhibitors of TGF-β receptors, modulators of intracellular kinases such as ERK or Smad, RNA-based approaches to silence pro-fibrotic transcripts and delivery of antifibrotic cytokines. Physical modalities—including high-intensity focused ultrasound and photobiomodulation—have emerged as non-invasive means to rebalance matrix turnover. Nanoparticle-mediated phototherapy offers precise control of signalling pathways, while lipid-based carriers deliver prostaglandins or nucleic acids to dermal cells. Taken together, these advances hold promise for conditions ranging from keloids and scleroderma to age-related dermal atrophy, with the ultimate goal of restoring normal tissue architecture and function.

Research from Nature Portfolio

Recent studies have demonstrated that near-infrared-emitting silver sulfide nanoparticles can activate TGF-β signalling in both human keratinocytes and dermal fibroblasts, driving collagen type I and metalloproteinase inhibitor expression via enhanced Smad2/3 phosphorylation. Lithium doping of these nanoparticles further augments photoluminescence and magnifies Smad activation, resulting in a marked increase in extracellular matrix assembly. This photobiomodulation strategy represents a novel, light-triggered approach to stimulate reparative collagen production in fibrotic or aged skin models without genetic modification.

Fibrotic Mechanisms and Therapeutic Strategies in Skin Disorders publication trend

The graph below shows the total number of articles in fibrotic mechanisms and therapeutic strategies in skin disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Fibrosis: Pathological accumulation of extracellular matrix proteins leading to tissue stiffening and scarring.

Fibroblast: Resident dermal cell responsible for synthesis of collagen and other matrix components.

Keratinocyte: Predominant epidermal cell that influences dermal remodelling through cytokine release.

TGF-β signalling: Cytokine-mediated pathway that induces Smad2/3 phosphorylation and drives pro-fibrotic gene transcription.

Smad proteins: Intracellular mediators that translocate to the nucleus upon TGF-β receptor activation to regulate transcription.

Photobiomodulation: Therapeutic use of non-ionising light to modulate cellular signalling and function.

Caveolin-1: Membrane scaffolding protein that regulates signal transduction and cellular senescence.

ERK/Ets-1 signalling: Kinase pathway culminating in activation of the Ets-1 transcription factor, which influences collagen gene expression.

References

1. Active synthesis of type I collagen homotrimer in Dupuytren’s fibrosis is unaffected by anti–TNF-α treatment. JCI Insight (2025).
2. High-Intensity Focused Ultrasound Increases Collagen and Elastin Fiber Synthesis by Modulating Caveolin-1 in Aging Skin. Cells (2023).
3. Lipo-PGE1 suppresses collagen production in human dermal fibroblasts via the ERK/Ets-1 signaling pathway. PLOS ONE (2017).
4. Near-infrared-emitting nanoparticles activate collagen synthesis via TGFβ signaling. Scientific Reports (2020).