Protein driver of cutaneous radiotherapy damage identified

DKK3 in keratinocytes orchestrates radiation-induced skin hyperplasia, dermatitis, and fibrosis. Radiation-induced reactive oxygen species (ROS) increase DKK3 expression in keratinocytes, which subsequently activates canonical Wnt signaling through autocrine TGF-β signaling. Elevated DKK3 levels in keratinocytes drive hyperproliferation and hyperplasia, promoting the polarization of macrophages toward a profibrotic phenotype. These polarized macrophages, in turn, upregulate fibrosis-associated factors in myofibroblasts, contributing to the fibrotic response. Li, L., Lopez Perez, R., Shehzad, K. et al. https://doi.org/10.1038/s41392-025-02541-z

A team from Ludwig Maximilian University of Munich (LMU) has identified a protein called Dickkopf 3 (DKK3) as a main cause of long-term skin damage after radiotherapy–a decisive step toward the development of novel, more targeted therapy options. The team included immunologist Professor Peter Nelson, PhD, (LMU University Hospital) and Roger Sandhoff and Peter E. Huber, MD from the German Cancer Research Center (DKFZ).

The findings were published in Signal Transduction and Targeted Therapy.

By investigating mouse models, human cells, and human tissue samples, the researchers demonstrated that DKK3 is activated after radiotherapy in a subset of skin cells responsible for skin renewal. This activity triggers a chain reaction which promotes inflammation and the formation of scar-like tissue, leading to chronic skin damage. The work of LMU students Li Li and Khuram Shehzad drove the key findings. Their efforts were essential in identifying DKK3 as the critical molecular mediator and in establishing the mechanistic framework presented in the paper.

“We also observed similar processes in the kidney,” says Dr. Nelson, in a press release. “This indicates that the activation of DKK3 is a fundamental mechanism that promotes fibrosis in various tissues.”

According to the researchers, these findings underscore that DKK3 represents a promising new treatment target.

“Drugs that block DKK3 could one day help prevent or reduce long-term skin damage after radiotherapy and thus improve the quality of life of cancer patients and survivors,” says Dr. Nelson. The researchers are also currently investigating whether this approach could also contribute to the prevention of scar formation in other organs.