The GPR120 agonist TUG-891 mitigates ischemic brain injury by attenuating endoplasmic reticulum stress and apoptosis via the PI3K/AKT signaling pathway

  • Neurotherapeutics. 2025 Sep 6:e00735. doi: 10.1016/j.neurot.2025.e00735.
Panxi Sun  1 ,  Lili Wei  2 ,  Xue Qin  2 ,  Jia Luo  2 ,  Dongsheng Fan  3 ,  Yong Chen  4
Affiliations
  • 1. Department of Neurology, Peking University Third Hospital, Beijing, 100191, China; Ministry-of-Education Key Laboratory of Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832000, China.
  • 2. Ministry-of-Education Key Laboratory of Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832000, China.
  • 3. Department of Neurology, Peking University Third Hospital, Beijing, 100191, China; Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, 100191, China; Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, 100191, China. Electronic address: [email protected].
  • 4. Department of Neurology, Peking University Third Hospital, Beijing, 100191, China; Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, 100191, China; Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, 100191, China. Electronic address: [email protected].
PMID: 40915963 DOI: 10.1016/j.neurot.2025.e00735
Abstract

Extensive research has confirmed that omega-3 fatty acids provide cardiovascular protection primarily by activating the G protein-coupled receptor 120 (GPR120) signaling pathway. However, natural activators of this receptor often lack sufficient strength and precision. TUG-891, a recently synthesized selective GPR120 activator, has displayed significant therapeutic potential in multiple disease. This investigation seeks to evaluate the neuroprotective effects of TUG-891 against ischemic cerebral injury. To this end, an in vivo murine model of distal middle cerebral artery occlusion (dMCAO) was employed, alongside an in vitro model utilizing oxygen-glucose deprivation/reperfusion in HT22 ​cells. The results indicated that TUG-891 significantly enhanced neurological function, reduced the volume of cerebral infarction, and alleviated pathological damage following dMCAO. Moreover, TUG-891 demonstrated a significant reduction in oxidative stress levels, a decrease of markers related to endoplasmic reticulum (ER) stress, and the modulation of critical apoptotic regulators, thereby inhibiting Apoptosis in both in vivo and in vitro settings. Additionally, TUG-891 was found to affect the PI3K/Akt signaling pathway, with the application of the inhibitor LY294002 negating the protective effects of TUG-891 in vitro. This comprehensive study reveals TUG-891's therapeutic potential for ischemic stroke through multi-target mechanisms involving oxidative stress mitigation, ER stress regulation, and survival pathway activation. The consistent neuroprotection observed across biological models underscores its translational value for further clinical development.

Keywords
Apoptosis; Endoplasmic reticulum stress; GPR120; Ischemic stroke; PI3K/AKT signaling pathway; TUG-891.
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