ORIGINAL RESEARCH article
Front. Mol. Neurosci.
Sec. Molecular Signalling and Pathways
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1617543
S-9-PAHSA ameliorates cognitive decline in a Type 2 Diabetes mouse model by inhibiting oxidative stress and apoptosis via CAⅢ modulation
Provisionally accepted
Xin-Ru Wang1,2Shan-Shan Huang1
Jin-Hong Lin3Jian-Tao Wang1Jiao-Qi Ren1
Cheng-Feng He4
Wen-Jiao Xue4Yin Wang1Xue-Chun Wang1Yan-Li Zhang1Ji-Chang Xiao3*
Jing-Chun Guo4*
Hou-Guang Zhou1*- 1Huashan Hospital, Fudan University, Shanghai, Shanghai Municipality, China
- 2Qilu Hospital of Shandong University, Jinan, China
- 3Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (CAS), Shanghai, Shanghai Municipality, China
- 4Fudan University, Shanghai, Shanghai Municipality, China
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Purpose: S-palmitic acid-9-hydroxy stearic acid (SP), a newly characterized endogenous lipid with multifaceted biological activities, is poised to shed light on its potential in diabetes-related cognitive disorder (DRCD). This study aims to uncover the effects of SP on DRCD and the underlying mechanisms. Methods: C57BL/6 mice were fed with high-fat diet for five months to induce type 2 diabetes mellitus (T2DM). Subsequently, they received bilateral hippocampal injections of adeno-associated virus (AAV) carrying carbonic anhydrase Ⅲ (CAⅢ) shRNA or control shRNA. Following one-month treatment with SP or vehicle, cognitive function was assessed using the Morris water maze and Y-maze tests. Oxidative stress and apoptosis were measured by Enzyme-linked Immunosorbent Assay (ELISA), and hippocampal neuronal morphology was examined through HE, Nissl, or NeuN staining. RNA sequencing (RNA seq), cell viability, tetramethylrhodamine ethyl ester (TMRE) staining, and mitoSOX assays were also performed in cultured PC12 cells. Results: Our findings demonstrated that CAⅢ played a pivotal role in enhancing cognitive function in T2DM mice by improving spatial memory. SP ameliorated hippocampal injury by CAⅢ-mediated AMPK/Sirt1/PGC1α pathway, Bcl-2/Bax ratio elevation, and cleaved-Caspase 3 reduction. CAⅢ participated in various biological processes in the effects of SP on PC12 cells, including cell viability, lactate dehydrogenase (LDH) release, antioxidant enzymes, the maintenance of mitochondrial membrane potential, and the reduction of mitochondrial reactive oxygen species (ROS). Conclusions: Our study revealed that CAⅢ was integral to the effects of SP on DRCD, suggesting its potential as a therapeutic target for DRCD.
Keywords: S-9-PAHSA, diabetes-associated cognitive disorder, Oxidative Stress, Mitochondrial dysfunction, CAIII
Received: 14 May 2025; Accepted: 29 Jul 2025.
Copyright: © 2025 Wang, Huang, Lin, Wang, Ren, He, Xue, Wang, Wang, Zhang, Xiao, Guo and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ji-Chang Xiao, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (CAS), Shanghai, 200032, Shanghai Municipality, China
Jing-Chun Guo, Fudan University, Shanghai, 200433, Shanghai Municipality, China
Hou-Guang Zhou, Huashan Hospital, Fudan University, Shanghai, Shanghai Municipality, China
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