Inhibition of Shh Signaling through MAPK Activation Controls Chemotherapy-Induced Alopecia

J Invest Dermatol. 2021 Feb;141(2):334-344. doi: 10.1016/j.jid.2020.05.118. Epub 2020 Jul 16.


Chemotherapy-induced hair loss (alopecia) (CIA) remains a major unsolved problem in clinical oncology. CIA is often considered to be a consequence of the antimitotic and apoptosis-promoting properties of chemotherapy drugs acting on rapidly proliferating hair matrix keratinocytes. Here, we show that in a mouse model of CIA, the downregulation of Shh signaling in the hair matrix is a critical early event. Inhibition of Shh signaling recapitulated key morphological and functional features of CIA, whereas recombinant Shh protein partially rescued hair loss. Phosphoproteomics analysis revealed that activation of the MAPK pathway is a key upstream event, which can be further manipulated to rescue CIA. Finally, in organ-cultured human scalp hair follicles as well as in patients undergoing chemotherapy, reduced expression of SHH gene correlates with chemotherapy-induced hair follicle damage or the degree of CIA, respectively. Our work revealed that Shh signaling is an evolutionarily conserved key target in CIA pathobiology. Specifically targeting the intrafollicular MAPK-Shh axis may provide a promising strategy to manage CIA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alopecia / chemically induced
  • Alopecia / pathology*
  • Animals
  • Antineoplastic Agents / adverse effects*
  • Cells, Cultured
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Gene Expression Profiling
  • Hair Follicle / drug effects*
  • Hair Follicle / pathology
  • Hedgehog Proteins / analysis
  • Hedgehog Proteins / metabolism*
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Primary Cell Culture
  • Proteomics
  • Scalp / cytology
  • Scalp / pathology


  • Antineoplastic Agents
  • Hedgehog Proteins
  • SHH protein, human
  • Shh protein, mouse