An Autophagy-Associated MITF–GAS5–miR-23 Loop Attenuates Vascular Oxidative and Inflammatory Damage in Sepsis
Open accessAbstract
Background: Sepsis induces GAS5 expression in the vascular endothelium, but the molecular mechanism is unclear, as is the role of GAS5 in sepsis. Methods and results: We observed that GAS5 expression in the endothelium was significantly upregulated in a sepsis mouse model. ChIP-PCR and EMSA confirmed that the oxidative stress (OS)-activated MiT–TFE transcription factor (MITF, TFE3, and TFEB)-mediated GAS5 transcription. In vitro, GAS5 overexpression attenuated OS and inflammation in endothelial cells (ECs) while maintaining the structural and functional integrity of mitochondria. In vivo, GAS5 reduced tissue ROS levels, maintained vascular barrier function to reduce leakage, and ultimately attenuated sepsis-induced lung injury. Luciferase reporter assays revealed that GAS5 protected MITF from degradation by sponging miR-23, thereby forming a positive feedback loop consisting of MITF, GAS5, and miR-23. Despite the fact that the OS-activated MITF–GAS5–miR-23 loop boosted MITF-mediated p62 transcription, ECs do not need to increase mitophagy to exert mitochondrial quality control since MITF-mediated Nrf2 transcription exists. Compared to mitophagy, MITF-transcribed p62 prefers to facilitate the autophagic degradation of Keap1 through a direct interaction, thereby relieving the inhibition of Nrf2 by Keap1, indicating that MITF can upregulate Nrf2 at both the transcriptional and posttranscriptional levels. Following this, ChIP-PCR demonstrated that Nrf2 can also transcribe MITF, revealing that there is a reciprocal positive regulatory association between MITF and Nrf2. Conclusion: In sepsis, the ROS-activated MITF–GAS5–miR-23 loop integrated the antioxidant and autophagy systems through MITF-mediated transcription of Nrf2 and p62, which dynamically regulate the level and type of autophagy, as well as exert antioxidant and anti-inflammatory effects.
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In a sepsis mouse model, the MITF-GAS5-miR-23 positive feedback loop can alleviate vascular oxidation and inflammatory damage in sepsis and maintain vascular barrier function.
“In a sepsis mouse model of systemic inflammatory disease induced by pathogen invasion, it was confirmed through chip PCR that the positive feedback loop, called MITF-GAS5-miR-23, which consists of miR-23 and the autophagy-related Mit-TFE transcription factor activated by oxidative stress (OS) and GAS5, can alleviate vascular oxidation and inflammatory damage in sepsis and maintain vascular barrier”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [35]
Results §3.7 reports that, in septic mice, MITF or GAS5 overexpression lowered lung ROS, stabilized endothelial junctions, and alleviated barrier dysfunction; it also reports regulation of the inflammatory response. The citing sentence overstates what ChIP-PCR established: the Abstract says ChIP-PCR confirmed transcriptional regulation of GAS5, while the protective effects were assessed in other experiments. Page numbers were not provided in our copy. (LLM, conf=0.86)
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Epigenetic Regulation by lncRNA GAS5/miRNA/mRNA Network in Human Diseases
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- Authors
- Cheng, J., Ding, C., Tang, H., Zhou, H., Wu, M., & Chen, Y.
- Affiliations
- Second Affiliated Hospital of Chongqing Medical University (CN)
- Chongqing Medical University (CN)
- Army Medical University (CN)
- Department of Vascular Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
- Corresponding author
- Chen, Yikuan
- Venue
- Biomedicines
- Publisher
- MDPI AG
- Published
- 2023-06-24
- Volume
- 11
- Issue
- 7
- Pages
- 1811
- ISSN
- 2227-9059 (ISSN-L)
- PMC
- PMC10376991
- OpenAlex
- W4382136063
- Semantic Scholar
- aebc849c2e4a11561d970bc699a4d59b56f3a458
- Cited by
- 5
- References
- 44
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicines (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81470583, CSTB2022NSCQ-MSX0805)
- Natural Science Foundation of ChongQing (81470583, CSTB2022NSCQ-MSX0805)
- Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University (81470583, CSTB2022NSCQ-MSX0805)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- sepsis, MITF, GAS5, miR-23, autophagy, oxidative stress, vascular endothelium, Nrf2, p62, Keap1, mitophagy, positive feedback loop, sepsis-induced lung injury, vascular barrier function, inflammation
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