2. Academic Validation
  3. Mechanism of lncRNA gadd7 regulating mitofusin 1 expression by recruiting LSD1 to down-regulate H3K9me3 level, and mediating mitophagy in alveolar type II epithelial cell apoptosis in hyperoxia-induced acute lung injury

Mechanism of lncRNA gadd7 regulating mitofusin 1 expression by recruiting LSD1 to down-regulate H3K9me3 level, and mediating mitophagy in alveolar type II epithelial cell apoptosis in hyperoxia-induced acute lung injury

  • Cell Biol Toxicol. 2025 Apr 29;41(1):77. doi: 10.1007/s10565-025-10021-x.
Guoyue Liu 1 2,  Guiyang Jia 1 2,  Yingcong Ren 2,  Cunzhi Yin 1,  Xuan Xiao 1,  Hang Wu 1,  Jun Liu 3,  Miao Chen 4
Affiliations

Affiliations

  • 1 Intensive Care Unit, The Second Affiliated Hospital of Zunyi Medical University, Intersection of Xinlong Avenue and Xinpu Avenue, Xinpu New District, Zunyi, 563000, Guizhou, China.
  • 2 Graduate School, Zunyi Medical University, No. 6, Xuefu West Road, Xinpu New District, Zunyi, 563000, Guizhou, China.
  • 3 Department of Preventive Medicine, School of Public Health, Zunyi Medical University, No. 6, Xuefu West Road, Xinpu New District, Zunyi, 563000, Guizhou, China. liujun_zmc@sina.com.
  • 4 Intensive Care Unit, Affiliated Hospital of Zunyi Medical University, No.149, Dalian Road, Huichuan District, Zunyi, Guizhou, China. chenmiao64@163.com.
PMID: 40301157 DOI: 10.1007/s10565-025-10021-x
Abstract

Objective: Hyperoxic exposure induces acute lung injury (ALI). We analyzed the mechanism of long non-coding RNA (lncRNA) growth-arrested DNA damage-inducible gene 7 (gadd7) regulating mitofusin 1 (MFN1) in Hyperoxia-induced ALI (HALI) type II alveolar epithelial cell (AEC II) Apoptosis.

Methods: The HALI rat model was generated using hyperoxic induction and treated with shRNA-gadd7 and rapamycin (Rapa), with ALI, apoptotic level, total protein concentration and total cell, neutrophil and macrophage counts assessed. The HALI cell model was developed on hyperoxia-induced RLE-6TN cells and processed with oe-MFN1, si-gadd7 and Rapa. Cell viability, Apoptosis, TOM20/LC3BII co-localization, mitochondrial membrane potential (MMP), superoxide dismutase activity, malonaldehyde, Reactive Oxygen Species (ROS), tumor necrosis factor-α, interleukin (IL)-10, IL-6, IL-1β, gadd7, MFN1, Cleaved Caspase-3, Cleaved poly (ADP-ribose) polymerase, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X, LC3BI/II, lysine-specific demethylase 1 (LSD1), p62, and H3K9me3 protein levels were measured. gadd7-LSD1 interaction was predicted and verified by RPISeq database, RIP, and RNA pull-down assay.

Results: In HALI rats, gadd7 was up-regulated in lung tissues, and gadd7 silencing alleviated oxidative stress, ALI and Apoptosis. gadd7 knockdown inhibited oxidative stress and Apoptosis though MFN1, and mediated Mitophagy (evidenced by diminished LC3BII/LC3BI ratio, TOM20/LC3BII co-localization and ROS level, and elevated p62 level and MMP), which were reversed by Mitophagy activation. By recruiting LSD1 to down-regulate H3K9me3 level and promote MFN1 expression, gadd7-mediated Mitophagy affected ALI and Apoptosis in HALI rats.

Conclusion: LncRNA gadd7 regulated MFN1 expression by recruiting LSD1 to down-regulate H3K9me3 level and mediate Mitophagy, thereby promoting AEC II Apoptosis in HALI.

Keywords

Alveolar type II epithelial cells; Apoptosis; Epigenetics; Growth-arrested DNA damage-inducible gene 7; H3K9me3; Hyperoxia-induced acute lung injury; Lysine-specific demethylase 1; Mitofusin 1; Mitophagy.

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