EDN1 and pachyonychia congenita: Using data obtained from assessments of EDN1 plasma levels and pain severity scores in PC patients, combined with in vivo, ex vivo, and in vitro experimental data from mice on the effects and mode of action of this peptide, our study suggests that EDN1 could mediate pain in PC by triggering visceral hypersensitivity and alterations in intestinal motility via direct activation of the EDNRs to induce calcium ion mobilization and activation of the pain signaling pathway in nociceptive fibers.