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Background <p>Hair follicle stem cells (HFSCs) in androgenetic alopecia (AGA) patients exhibit functional impairment, reduced quantity, dysregulation, and androgen sensitivity, which hinder therapeutic strategies targeting HFSCs activation for hair regeneration. This study aims to elucidate the molecular mechanisms underlying HFSCs dysfunction in AGA and identify novel therapeutic targets.</p> Methods <p>We compared the expression of insulin-like growth factor 1 (IGF-1) in hair follicle tissues between AGA patients and healthy controls, analyzing transcriptional and protein-level differences. Bioinformatics, luciferase assays, and correlation analyses were employed to investigate the AR/miR-128-3p/IGF-1 pathway. Mechanistic studies were conducted using dermal papilla cells (DPCs) from both AGA patients and normal donors, which included RNA interaction assays and functional validation. Furthermore, the mechanism was validated by assessing the phenotypic changes in HFSCs co-cultured experiments. In vivo experiments in AGA mice were performed to evaluate hair follicle regeneration following ASLNC168501 overexpression.</p> Results <p>IGF-1 expression was markedly reduced in hair follicles of AGA patients, with transcriptional alterations occurring later than changes at the protein-level alterations. Dysregulation of the AR/miR-128-3p/IGF-1 pathway in DPCs was identified as a key driver of HFSCs dysfunction: AR transcriptionally activates miR-128-3p, which in turn suppresses IGF-1 by binding to its 3’UTR. Consequently, the ability of IGF-1 to sustain and support HFSCs activity is impaired. The endogenous ASLNC168501 functions as a ceRNA, sequestering miR-128-3p and thereby restoring IGF-1 expression and secretion. Exogenous overexpression of ASLNC168501 in DPCs significantly promoted the self-renewal, proliferative and differentiation potential of co-cultured HFSCs in vitro and reversed hair follicle atrophy in AGA mice.</p> Conclusions <p>Our findings demonstrate that loss of ASLNC168501 accelerates the progression of AGA by activating AR/miR-128-3p/IGF-1 pathway activation. Acting as a pathway-independent RNA, ASLNC168501 holds a target significant therapeutic potential for restoring HFSCs function and promoting hair follicle regeneration. This finding highlights a novel molecular target and contributes to the advancement of precision medicine strategies for androgen-related alopecia.</p>

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Role of ASLNC168501 in regulating hair follicle stem cell activity via the AR/miR-128-3p/IGF-1 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月27日

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  • Xuewen Chen,
  • Jingxiu Chai,
  • Xuan Wang,
  • Leimeng Gan,
  • Qing Zhang,
  • Hao Luo,
  • Ling Wu,
  • Yuchong Chen

摘要

Background

Hair follicle stem cells (HFSCs) in androgenetic alopecia (AGA) patients exhibit functional impairment, reduced quantity, dysregulation, and androgen sensitivity, which hinder therapeutic strategies targeting HFSCs activation for hair regeneration. This study aims to elucidate the molecular mechanisms underlying HFSCs dysfunction in AGA and identify novel therapeutic targets.

Methods

We compared the expression of insulin-like growth factor 1 (IGF-1) in hair follicle tissues between AGA patients and healthy controls, analyzing transcriptional and protein-level differences. Bioinformatics, luciferase assays, and correlation analyses were employed to investigate the AR/miR-128-3p/IGF-1 pathway. Mechanistic studies were conducted using dermal papilla cells (DPCs) from both AGA patients and normal donors, which included RNA interaction assays and functional validation. Furthermore, the mechanism was validated by assessing the phenotypic changes in HFSCs co-cultured experiments. In vivo experiments in AGA mice were performed to evaluate hair follicle regeneration following ASLNC168501 overexpression.

Results

IGF-1 expression was markedly reduced in hair follicles of AGA patients, with transcriptional alterations occurring later than changes at the protein-level alterations. Dysregulation of the AR/miR-128-3p/IGF-1 pathway in DPCs was identified as a key driver of HFSCs dysfunction: AR transcriptionally activates miR-128-3p, which in turn suppresses IGF-1 by binding to its 3’UTR. Consequently, the ability of IGF-1 to sustain and support HFSCs activity is impaired. The endogenous ASLNC168501 functions as a ceRNA, sequestering miR-128-3p and thereby restoring IGF-1 expression and secretion. Exogenous overexpression of ASLNC168501 in DPCs significantly promoted the self-renewal, proliferative and differentiation potential of co-cultured HFSCs in vitro and reversed hair follicle atrophy in AGA mice.

Conclusions

Our findings demonstrate that loss of ASLNC168501 accelerates the progression of AGA by activating AR/miR-128-3p/IGF-1 pathway activation. Acting as a pathway-independent RNA, ASLNC168501 holds a target significant therapeutic potential for restoring HFSCs function and promoting hair follicle regeneration. This finding highlights a novel molecular target and contributes to the advancement of precision medicine strategies for androgen-related alopecia.