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A Glucocorticoid-KLF9-CHCHD10 Axis Governs Mitochondrial Resilience in Radiation-Induced Lung Injury
Peixin Tan1, Kunpeng Wu2, Mengsi Liu3
1Department of Radiation Oncology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Background:
Radiation-induced lung injury (RILI) is a major dose-limiting complication of thoracic radiotherapy. Although mitochondrial damage has been implicated in RILI, the endogenous transcriptional programs that restore mitochondrial structure and bioenergetic function after irradiation remain poorly defined.
Methods:
To identify radiation-sensitive mitochondrial regulators in type II alveolar epithelial cells (AT2), we integrated single-cell RNA sequencing data from irradiated lungs with weighted gene co-expression network analysis. Transcription factor prediction, multi-omics correlation analysis, and molecular docking were used to construct upstream regulatory networks. The functional relevance of the KLF9-CHCHD10 axis was validated using mitochondrial ultrastructure analysis, oxygen consumption assays, apoptosis detection, gene expression profiling, and CHCHD10 loss- and gain-of-function experiments performed in vitro and in vivo.
Results:
Single-cell transcriptomic profiling identified CHCHD10, a mitochondrial cristae-associated protein, as a central radiation-sensitive hub in AT2 cells. Irradiation reduced CHCHD10 expression and disrupted mitochondrial homeostasis, leading to mitochondrial fragmentation, impaired oxygen consumption, enhanced epithelial apoptosis, activation of the Ppia-CD147 inflammatory signaling axis, and suppression of PPARγ-associated metabolic homeostasis. Mechanistically, KLF9 directly activated CHCHD10 transcription, whereas irradiation suppressed the KLF9-CHCHD10 circuit. Restoration of this pathway by CHCHD10 overexpression or glucocorticoid intervention preserved mitochondrial cristae integrity, improved bioenergetic recovery, and enhanced epithelial cell survival. In vivo, lung-specific CHCHD10 knockdown aggravated radiation-induced parenchymal remodeling and fibrotic deposition and partially weakened the protective efficacy of glucocorticoids.
Conclusion:
This study defines a GC-KLF9-CHCHD10 axis that restores mitochondrial ultrastructure and bioenergetics after radiation, positioning mitochondrial resilience as an active epithelial protective program in RILI. Antioxid. Redox Signal. 00, 000-000.
