Citation: Fan Yang, Tingting Fu, Wandi Xiong, Shuting Zhang, Junjie Wang, Wenjun Shan, Xinyi Chen, Mingbin Chen, Qi Guo, Jinzhuo Li, Junyi Li, Jingru Liu, Jin Liu, Yong Rao, Zhongping Jiang, Congjun Xu, Ling Huang. Discovery of marine-derived ent–atisane diterpenoid lead compounds targeting sEH for Alzheimer’s disease therapy[J]. Chinese Chemical Letters, ;2026, 37(8): 111773. doi: 10.1016/j.cclet.2025.111773 shu

Discovery of marine-derived ent–atisane diterpenoid lead compounds targeting sEH for Alzheimer’s disease therapy

Fan Yang ^{a, 1} ,
Tingting Fu ^{a, b, 1} ,
Wandi Xiong ^{a, 1} ,
Shuting Zhang ^a ,
Junjie Wang ^a ,
Wenjun Shan ^c ,
Xinyi Chen ^a ,
Mingbin Chen ^a ,
Qi Guo ^{a, d} ,
Jinzhuo Li ^{a, d} ,
Junyi Li ^a ,
Jingru Liu ^a ,
Jin Liu ^a ,
Yong Rao ^a ,
Zhongping Jiang ^{a, *,} ,
Congjun Xu ^{a, *,} ,
Ling Huang ^{a, *,}

a.
Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
b.
NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, China
c.
Shanghai Haiyan Pharmaceutical Technology Co., Ltd., Shanghai 201203, China
d.
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China

zpjiang@hainanu.edu.cn

congjunxu@hainanu.edu.cn

Linghuang@hainanu.edu.cn

Received Date: 24 July 2025
Revised Date: 28 August 2025
Accepted Date: 29 August 2025
Available Online: 29 August 2025

Figures(4)

Accumulating evidence highlights the therapeutic potential of soluble epoxide hydrolase (sEH) inhibitors with anti-inflammatory and neuroprotective properties for Alzheimer’s disease (AD). In this work, an ent–atisane diterpenoid J12 was identified as a hit compound against sEH with moderate inhibitory activity from five distinct series of compounds (J1–J44) isolated from Excoecaria agallocha L. After rational structural modification, a novel sEH inhibitor HXY14 with improved sEH inhibitory activity (half maximal inhibitory concentration (IC₅₀) = 1.6 µmol/L, 10-fold compared to J12) was obtained. The cellular thermal shift assay (CETSA) demonstrated direct binding of HXY14 to sEH. In an Aβ-induced neuroinflammation cell model, treatment with HXY14 increased epoxyeicosatrienoic acids (EETs) levels, leading to reduced neuroinflammation and concomitant neuroprotection. HXY14 could ameliorate memory impairment and exhibited cognitive improvement in Aβ_1–42-induced AD model and exhibited preferable safety in vivo. Treatment with HXY14 significantly decreased the expression levels of inflammatory factors and attenuated microglia activation, thereby inhibiting neuroinflammation. Furthermore, HXY14 could promote neuroprotection and alleviate synaptic dysfunction in AD model mice. This study expands the discovery of novel naturally derived sEH inhibitors and provides evidence for the utility of sEH inhibitors for AD therapy.
- sEH inhibitor,
- Marine,
- Natural products,
- Diterpenoid,
- Alzheimer’s disease
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