2. Academic Validation
  3. S100A8 induces cyclophosphamide-induced alopecia via NCF2/NOX2-mediated ferroptosis

S100A8 induces cyclophosphamide-induced alopecia via NCF2/NOX2-mediated ferroptosis

  • Free Radic Biol Med. 2025 Feb 11:230:112-126. doi: 10.1016/j.freeradbiomed.2025.02.014.
Wen Xu 1,  Yujie Li 2,  Sheng Wan 3,  Beilei Zhang 2,  Dongfan Wei 1,  Hongyan Zhang 3,  Xiaofan Jin 1,  Bo Xie 3,  Cuiping Guan 3,  Xiuzu Song 4
Affiliations

Affiliations

  • 1 School of Medicine, Zhejiang University, Hangzhou, 310009, China; Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 2 Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Graduate School, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 3 Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 4 Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. Electronic address: songxiuzu@sina.com.
PMID: 39947495 DOI: 10.1016/j.freeradbiomed.2025.02.014
Abstract

Chemotherapy-induced alopecia (CIA), commonly associated with agents such as cyclophosphamide (CYP), is a prevalent and distressing side effect of numerous chemotherapeutic treatments, significantly impacting patients' quality of life. S100A8, a calcium-binding protein involved in inflammatory responses and oxidative stress regulation, plays a pivotal role in cellular homeostasis. In this study, we investigated the involvement of S100A8 in Ferroptosis within a CYP-induced CIA mouse model. We found that CYP treatment upregulated S100A8, NCF2, and NOX2 while reducing GPX4 levels in hair follicles, indicating elevated oxidative stress and Ferroptosis. Administration of the S100A8 inhibitor paquinimod (PAQ) alleviated alopecia and decreased markers of oxidative stress and Ferroptosis. In vitro experiments using human outer root sheath keratinocytes (ORSKs) confirmed that S100A8 promotes Ferroptosis via the NCF2/NOX2 pathway, as inhibition of NCF2 or NOX2 reversed these effects. These findings suggest that targeting the S100A8-NCF2/NOX2 axis may provide a novel therapeutic strategy for mitigating CIA induced by various chemotherapeutic agents.

Keywords

Chemotherapy-induced alopecia; Cyclophosphamide; Ferroptosis; Oxidative stress; S100A8.

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