Keloid scars are benign skin neoplasms that arise from impaired wound-healing processes. Despite decades of research, the mechanisms underlying their formation remain incompletely understood, and the efficacy of existing treatment modalities is often limited.

Traditionally, research attention has focused on fibroblasts and excessive collagen synthesis. However, clinical observations have long pointed to a link between pigmentation and keloid risk: individuals with darker skin (phototypes IV–VI) experience these scars significantly more frequently and with greater severity. A new study published in Signal Transduction and Targeted Therapy offers a fundamentally new perspective on keloid pathogenesis, placing melanin and its influence on cellular metabolism at the center of the process [1].

What the Authors Did

The research team conducted a comprehensive analysis of human keloid tissue samples using advanced imaging and molecular analysis methods. The scientists assessed melanin content via Masson-Fontana staining, examined the state of the basal membrane, and studied interactions between epidermal and dermal cells. The study employed cell cultures (in vitro), human skin explants (ex vivo), and an immunodeficient nude mouse model with transplanted human keloid fragments—the absence of an immune response in these animals allows the study of human tissues in a living organism without the risk of rejection.

Key Results: Melanin Is Elevated and Correlates with Disease Severity

Analysis revealed that melanin content in keloid tissue was significantly higher than in normal skin from the same donors. Moreover, pigmentation levels directly correlated with clinical scar severity as measured by the Vancouver Scar Scale (VSS).

Researchers found that melanocytes in keloids are hyperreactive and that the basal membrane is severely damaged. This disruption of membrane integrity facilitates melanin "leakage" from the epidermis into the dermis, where it comes into direct contact with fibroblasts.

How Melanin "Switches" Fibroblasts into Fibrogenesis Mode

Experiments demonstrated that dermal fibroblasts actively take up melanin. Once inside the cell, it stimulates proliferation, migration, and collagen synthesis, including types I and III. Melanin acts as a signaling molecule that triggers pathological fibroblast activation, transforming them into myofibroblasts that form dense scar tissue.

The Paradox: More Iron, Less Ferroptosis

One of the most significant discoveries was the role of iron. Melanin can bind and retain metal ions. In keloid fibroblasts that had accumulated melanin, pronounced iron overload was observed. Normally, excess iron should lead to ferroptosis—programmed cell death caused by lipid peroxidation. However, melanin simultaneously activates protective systems (particularly the SLC7A11/GPX4 pathway) that render cells resistant to this form of cell death. As a result, fibroblasts do not die but continue to proliferate uncontrollably and synthesize matrix despite toxic iron levels.

Autocrine Effects in Melanocytes and Enhanced Melanin Transfer

Melanin affects not only fibroblasts but also melanocytes themselves. Through an autocrine mechanism, it stimulates further melanogenesis and enhances pigment transport to keratinocytes. This creates a vicious cycle: the more melanin is produced, the more severely the basal membrane is damaged, and the more actively fibrosis is stimulated in the dermis.

Therapeutic Component: Melanogenesis Inhibition

Given melanin's key role, the authors tested whether ML329, a small-molecule inhibitor, could block its synthesis by targeting the master regulator of melanogenesis, the MITF transcription factor. In experiments on nude mice with implanted human keloid fragments, application of ML329 led to a notable reduction in scar volume and decreased collagen density.

It is important to note that ML329 is currently an experimental research compound and is not approved for clinical use. The authors emphasize that neither the FDA (United States) nor the CFDA (China) has approved any specific drug for the treatment of keloids. Systemic MITF inhibition may have serious side effects, including an increased risk of vitiligo, effects on mast cells, and effects on bone regeneration. However, the researchers believe that applying such inhibitors directly to the scar area could minimize systemic risks and represent a promising treatment strategy.

Despite compelling data, the study has limitations. The majority of the work focused on patients with darker skin phototypes, and the mechanisms of keloid development in individuals with lighter skin may differ. Further investigation is needed into the precise pathways of melanin transport across the damaged basal membrane and the potential for direct modulation of ferroptosis for scar treatment.

What This May Mean for Practice

For practicing specialists, this study provides a scientific rationale for the importance of pigmentation control when working with scars. In the future, keloid treatment protocols may necessarily include agents that suppress melanocyte activity. Even today, when managing patients at risk of keloid formation (especially those with higher phototypes), heightened attention should be paid to ultraviolet protection and early correction of post-inflammatory hyperpigmentation, as these factors can sustain fibrosis.

References

1. Li Y., Li Y., Zhang J. et al. Increased melanin induces aberrant cell communication and fibrogenesis in keloids by causing iron overload and ferroptosis resistance. Sig Transduct Target Ther 2024; 9(1): 45. https://doi.org/10.1038/s41392-024-01754-x
2. Glass D.A. Current understanding of the genetic causes of keloid formation. J Investig Dermatol Symp Proc 2017; 18(2): S50–S53.
3. Wang Z., Chen X., Ni Z. et al. The role of ferroptosis in fibrosis-associated diseases. Front Cell Dev Biol 2022; 10: 801872.
4. Plikus M.V., Guerrero-Juarez C.F., Ito M. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 2017; 355(6326): 748–752.
5. D'Mello S.A., Finlay G.J., Baguley B.C. et al. Signaling pathways in melanogenesis. Int J Mol Sci 2016; 17(7): 1144.