MLPH-mediated activation of dermal papilla IGF-1 signaling drives human hair shaft elongation and anagen induction

Abstract

Introduction Hair loss (alopecia) is a multifactorial disorder that often causes distress. Approved therapies such as minoxidil and finasteride act indirectly and do not specifically target hair follicle (HF) cells. Erythropoietin (EPO), however, has been shown to activate dermal papilla (DP) cells via the erythropoietin receptor (EPOR), suggesting a potential role in hair follicle regeneration and hair growth. Objectives This study aimed to develop and validate Helix C-1–based EPO-derived peptides that activate DP cells and increase IGF-1 expression, while not inducing overt systemic erythropoietic effects (e.g., increases in red blood cell counts, reticulocytes, hemoglobin, or hematocrit) under the tested experimental conditions. Methods Peptides derived from the Helix C-1 region of EPO were synthesized and characterized by EPOR-binding affinity, CD spectroscopy, and ERK/AKT activation. In vitro, DP-cell metabolic activity, proliferation, and IGF-1 secretion were assessed. Ex vivo efficacy was evaluated by hair shaft elongation in hair follicle organ culture, and in vivo efficacy was tested in a murine depilation-induced anagen model with concurrent hematologic assessment to exclude erythropoiesis-related effects. Results The peptides increased DP-cell metabolic activity and proliferation, reduced oxidative stress, and enhanced IGF-1 production via EPOR-mediated ERK/AKT activation. They promoted hair shaft elongation ex vivo and promoted anagen entry in mice without significant changes in standard hematologic parameters under the tested dosing regimen. Conclusion These findings support the conclusion that MLPH promotes hair growth via an EPOR-linked, IGF-1–dependent mechanism in DP cells. Future pharmacokinetic and disease-model studies are warranted to evaluate its translational potential. © 2026 The Authors.