Work

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

Year: 2025

Type: article

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.

Source: Cell Biology and Toxicology

DOI: 10.1007/s10565-025-10021-x