Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome

Paul Hiebert*, Mateusz S. Wietecha, Michael Cangkrama, Eric Haertel, Eleni Mavrogonatou, Michael Stumpe, Heiko Steenbock, Serena Grossi, Hans Dietmar Beer, Peter Angel, Jürgen Brinckmann, Dimitris Kletsas, Jörn Dengjel, Sabine Werner

*Corresponding author for this work
9 Citations (Scopus)


Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer-associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor.

Original languageEnglish
JournalDevelopmental Cell
Issue number2
Pages (from-to)145-161.e10
Publication statusPublished - 16.07.2018

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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