KLF9 drives intermittent hypoxia-induced MASLD by suppressing the NR4A1–p38 MAPK hepatic metabolic axis

Background and Aims: Obstructive sleep apnea (OSA), characterized by recurrent episodes of intermittent hypoxia (IH), is increasingly recognized as a contributor to metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). However, the causal relationship and underlying molecular mechanisms linking IH and MASLD remain incompletely understood, hindering the development of effective therapeutic strategies. Approach and Results: We established murine and cellular models of IH and performed comprehensive metabolic and molecular profiling, including glucose and insulin tolerance tests, biochemical analyses, histology, lipidomics, real-time quantitative PCR, western blotting, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, ChIP assay, co-immunoprecipitation, and luciferase reporter gene assays, to investigate the impact of IH and the role of KLF9 in hepatic lipid metabolism. The findings showed IH exposure induced hepatic lipid accumulation and insulin resistance in both normal and obese mice, accompanied by transcriptional reprogramming of lipid metabolic pathways. Transcriptomic analysis identified KLF9 as significantly upregulated by IH treatment. Functional studies demonstrated that hepatic overexpression of KLF9 exacerbated, while its knockdown alleviated, IH-induced steatosis, lipogenesis, and inflammation. Mechanistically, KLF9 directly binds to a conserved GC-rich motif within the NR4A1 promoter, suppressing NR4A1 transcription and downstream p38 MAPK activation. Pharmacologic modulation of NR4A1 further confirmed its regulatory role in mediating KLF9-driven lipogenesis under IH. Conclusions: This study identifies KLF9 as a key transcriptional regulator driving IH-associated MASLD by repressing NR4A1 and inhibiting p38 MAPK signaling, thereby promoting hepatic lipogenesis. Targeting the KLF9–NR4A1 axis may offer a novel therapeutic approach for managing MASLD in patients with OSA and other hypoxia-related disorders.