Venlafaxine reverses chemotherapy-induced alopecia through epithelial and dermal reprogramming at single-cell...

Chemotherapy-induced alopecia (CIA) is a frequent and distressing adverse effect of cytotoxic cancer therapy that significantly affects patients' quality of life, yet its cellular mechanisms remain incompletely understood and effective pharmacological interventions are limited. Here, we combined single-cell RNA sequencing with in vivo mouse models and ex vivo human hair follicle organ culture to systematically characterize the cellular ecosystem underlying CIA. Our results demonstrate that CIA is not solely caused by apoptosis of rapidly proliferating epithelial cells but represents a coordinated multicompartmental dysfunction within the hair follicle niche. Cyclophosphamide treatment induces profound suppression of ribosomal biogenesis, cytoplasmic translation, mitochondrial oxidative phosphorylation, and Wnt-associated regenerative programs in hair matrix cells, indicating a functional metabolic arrest preceding overt epithelial cell loss. In parallel, dermal fibroblasts undergo inflammatory and stress-associated reprogramming accompanied by activation of IL-1, TNF, IL-6, and epithelial-mesenchymal transition signaling pathways. Chemotherapy also disrupts epithelial-mesenchymal communication through reduced expression of critical niche factors including FGF7, FGF10, and Slit2. Topical venlafaxine and its active metabolite desvenlafaxine preserved follicular architecture, suppressed apoptosis, and restored hair shaft elongation in both mouse CIA models and human hair follicle organ culture. At single-cell resolution, venlafaxine reversed epithelial translational shutdown, reactivated differentiation and Wnt signaling programs, and attenuated fibroinflammatory remodeling, thereby restoring paracrine niche signaling and matrix cell proliferation. Collectively, these findings redefine CIA as a disorder characterized by coordinated epithelial functional arrest and dermal inflammatory remodeling and identify venlafaxine as a potential pharmacological strategy to mitigate chemotherapy-associated hair loss.