A Glucocorticoid–KLF9–CHCHD10 Axis Governs Mitochondrial Resilience in Radiation-Induced Lung Injury

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.