KLF9 Links Intermittent Hypoxia to MASLD: Hepatology | July 2026

Introduction:

Obstructive sleep apnea (OSA) is increasingly recognized as an important metabolic risk factor due to recurrent episodes of intermittent hypoxia (IH). Clinical studies have linked OSA with metabolic dysfunction–associated steatotic liver disease (MASLD), but the molecular mechanisms underlying this association remain poorly understood. This study investigated how IH promotes hepatic steatosis and identified key transcriptional regulators driving MASLD progression.

Why was this study needed?

OSA is common in patients with obesity and MASLD, but the causal mechanisms remain unclear.

Understanding how intermittent hypoxia alters hepatic metabolism could identify new therapeutic targets.

The transcriptional pathways linking hypoxia to hepatic lipid accumulation have not been fully characterized.

Novel molecular targets are needed to treat MASLD associated with sleep-disordered breathing.

Results:

Using murine and cellular models of intermittent hypoxia, the investigators demonstrated that IH induced hepatic lipid accumulation, insulin resistance, and widespread reprogramming of hepatic lipid metabolism. Transcriptomic analyses identified KLF9 as a major hypoxia-responsive transcription factor. Functional experiments showed that hepatic overexpression of KLF9 markedly aggravated steatosis, lipogenesis, and inflammation, whereas KLF9 knockdown protected against IH-induced liver injury. Mechanistically, KLF9 directly suppressed NR4A1 transcription, resulting in inhibition of the NR4A1–p38 MAPK signaling pathway and enhanced hepatic lipogenesis. Pharmacologic modulation of NR4A1 further confirmed its central role in mediating the metabolic effects of KLF9 during intermittent hypoxia.

Clinical Impact:

This study provides mechanistic evidence linking OSA-induced intermittent hypoxia to MASLD progression through the KLF9–NR4A1–p38 MAPK pathway. These findings reinforce the importance of recognizing and treating sleep apnea in patients with MASLD and suggest that therapies targeting KLF9 or restoring NR4A1 signaling could represent novel approaches for managing hypoxia-associated fatty liver disease.

Bottom Line:

Intermittent hypoxia promotes MASLD by activating KLF9, which suppresses the NR4A1–p38 MAPK metabolic pathway, driving hepatic lipogenesis and inflammation. The KLF9–NR4A1 axis represents a promising therapeutic target for MASLD in patients with obstructive sleep apnea.