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已发表论文
GLX351322 负载的纳米颗粒通过抑制铁死亡和氧化应激缓解慢性应激诱导的抑郁行为
Authors Wang T, An J, Fu X, Sun J, Li H, Han X, Yang W
Received 21 July 2025
Accepted for publication 13 November 2025
Published 24 November 2025 Volume 2025:20 Pages 14033—14055
DOI https://doi.org/10.2147/IJN.S555165
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. RDK Misra
Tian Wang,1 Junyan An,2 Xiying Fu,3 Jiangjin Sun,1 Haiping Li,1,4 Xiaoou Han,1 Wei Yang1
1Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 3Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 4Department of Neurology, The Affiliated Hospital of Bei-Hua University, Jilin, Jilin Province, People’s Republic of China
Correspondence: Wei Yang, Email wyang2002@jlu.edu.cn
Purpose: Depression is a widespread neuropsychiatric disorder with limited treatment efficacy and frequent adverse effects. Ferroptosis, an iron-dependent and oxidative stress (OS) - related form of regulated cell death, is emerging as a key pathogenic mechanism in neurological diseases, yet its role in depression remains largely unexplored. This study aimed to evaluate the antidepressant and neuroprotective potential of GLX351322 (GLX), a selective inhibitor of NADPH oxidase 4 (NOX4), by formulating it into a nanocarrier system to overcome its pharmacokinetic limitations.
Methods: GLX was encapsulated into methoxy poly (ethylene glycol)-poly(ϵ-caprolactone) (mPEG-PCL) nanoparticles (GLX-NPs) via a simple nanoprecipitation method. Including particle size, zeta (ζ) potential, morphology, drug loading (DL), encapsulation efficiency (EE), biodistribution, and release efficiency, were characterized. In vivo, the antidepressant effect was assessed using a chronic unpredictable mild stress (CUMS) mouse model, while in vitro, the safety profile was evaluated in CORT-induced HT22 cells. Fluorescence, Quantitative real-time PCR (qRT-PCR), and Western blot (WB) experiments were conducted to explore the underlying neuroprotective mechanisms.
Results: The average particle size of GLX-NPs was 43.58 ± 3.09 nm, with a ζ potential of approximately − 12.13 ± 0.35 mV, a DL of 6.90%, and an EE of 88.79%. GLX-NPs increased the accumulation of the drug in brain tissues. In CUMS mice, GLX-NPs improved depressive-like behaviors and preserved hippocampal neuronal integrity. Mechanistically, GLX-NPs inhibited NOX4 expression, suppressed reactive oxygen species (ROS) production and lipid peroxidation, and activated the Nrf2/HO-1/GPX4 pathway to alleviate ferroptosis. Co-administration with ferroptosis inducers or Nrf2 inhibitors reversed these protective effects.
Conclusion: GLX-NPs effectively alleviate depressive-like behaviors by inhibiting neuronal ferroptosis and OS via modulation of the NOX4/Nrf2/HO-1/GPX4 signaling pathway. This study supports the therapeutic potential of GLX-NPs as a novel nanomedicine targeting ferroptosis in the treatment of depression.
Keywords: Depression, nanoparticle, oxidative stress, ferroptosis, NOX4
1Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 3Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 4Department of Neurology, The Affiliated Hospital of Bei-Hua University, Jilin, Jilin Province, People’s Republic of China
Correspondence: Wei Yang, Email wyang2002@jlu.edu.cn
Purpose: Depression is a widespread neuropsychiatric disorder with limited treatment efficacy and frequent adverse effects. Ferroptosis, an iron-dependent and oxidative stress (OS) - related form of regulated cell death, is emerging as a key pathogenic mechanism in neurological diseases, yet its role in depression remains largely unexplored. This study aimed to evaluate the antidepressant and neuroprotective potential of GLX351322 (GLX), a selective inhibitor of NADPH oxidase 4 (NOX4), by formulating it into a nanocarrier system to overcome its pharmacokinetic limitations.
Methods: GLX was encapsulated into methoxy poly (ethylene glycol)-poly(ϵ-caprolactone) (mPEG-PCL) nanoparticles (GLX-NPs) via a simple nanoprecipitation method. Including particle size, zeta (ζ) potential, morphology, drug loading (DL), encapsulation efficiency (EE), biodistribution, and release efficiency, were characterized. In vivo, the antidepressant effect was assessed using a chronic unpredictable mild stress (CUMS) mouse model, while in vitro, the safety profile was evaluated in CORT-induced HT22 cells. Fluorescence, Quantitative real-time PCR (qRT-PCR), and Western blot (WB) experiments were conducted to explore the underlying neuroprotective mechanisms.
Results: The average particle size of GLX-NPs was 43.58 ± 3.09 nm, with a ζ potential of approximately − 12.13 ± 0.35 mV, a DL of 6.90%, and an EE of 88.79%. GLX-NPs increased the accumulation of the drug in brain tissues. In CUMS mice, GLX-NPs improved depressive-like behaviors and preserved hippocampal neuronal integrity. Mechanistically, GLX-NPs inhibited NOX4 expression, suppressed reactive oxygen species (ROS) production and lipid peroxidation, and activated the Nrf2/HO-1/GPX4 pathway to alleviate ferroptosis. Co-administration with ferroptosis inducers or Nrf2 inhibitors reversed these protective effects.
Conclusion: GLX-NPs effectively alleviate depressive-like behaviors by inhibiting neuronal ferroptosis and OS via modulation of the NOX4/Nrf2/HO-1/GPX4 signaling pathway. This study supports the therapeutic potential of GLX-NPs as a novel nanomedicine targeting ferroptosis in the treatment of depression.
Keywords: Depression, nanoparticle, oxidative stress, ferroptosis, NOX4