Citation: Yongchuang Li, Haiyue Liu, Caixia Yin, Fangjun Huo. Nucleophilic substitution driven Cys specific-fast fluorescence response for visualizing correlation between Cys and AD mediated by ferroptosis[J]. Chinese Chemical Letters, ;2026, 37(7): 111750. doi: 10.1016/j.cclet.2025.111750 shu

Nucleophilic substitution driven Cys specific-fast fluorescence response for visualizing correlation between Cys and AD mediated by ferroptosis

Yongchuang Li ^a ,
Haiyue Liu ^a ,
Caixia Yin ^{b, *,} ,
Fangjun Huo ^{a, *,}

a.
Research Institute of Applied Chemistry, Shanxi University, Taiyuan 030006, China
b.
Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China

yincx@sxu.edu.cn

huofj@sxu.edu.cn

Received Date: 6 May 2025
Revised Date: 20 August 2025
Accepted Date: 22 August 2025
Available Online: 23 August 2025

Figures(6)

Cysteine (Cys), as a key precursor of glutathione (GSH) and an essential component of the thiol antioxidant system, plays a dual role in the pathological progression of Alzheimer’s disease (AD): it participates in antioxidant defense mechanisms while also potentially exacerbating neurological damage through metabolic dysregulation. Investigating the dynamic regulatory mechanisms of Cys in AD progression serves as a critical bridge linking oxidative stress, metabolic dysregulation, and neurodegenerative degeneration. High-resolution in vivo imaging of Cys dynamics in AD brains remains an unmet need. In view of the instability of the fluorescent probe of acrylyl group and the lack of specificity for Cys. This work introduced chlorine atoms into the probe structure, and achieved dual modifications: (1) Converting the nucleophilic addition mechanism into an S_N2 substitution; (2) modulating the conjugation effects between the formyl group and the three-position double bond. In this way, the stability of the probe, the high specificity of Cys, and the crossing of the blood-brain barrier are addressed. Through in situ imaging in AD models, we have demonstrated a pathological reduction in Cys levels during AD. Furthermore, as Cys serves as the core molecule in the regulation of ferroptosis, it was found that ferroptosis can mediate the down-regulation of Cys in AD through ferroptosis inducers and inhibitors. This study is not only to reveal the core pathological mechanism of AD, but to provide theoretical basis and technical support for early diagnosis, targeted therapy and personalized medicine.
- Cys,
- Alzheimer’s disease,
- Ferroptosis,
- GPX4,
- Fluorescence imaging
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