IL6 Derived from Macrophages under Intermittent Hypoxia Exacerbates NAFLD by Promoting Ferroptosis via MARCH3-Led...

Area of Science:

• Hepatology
• Sleep Medicine
• Cellular Biology

Background:

• Obstructive sleep apnea (OSA), marked by intermittent hypoxia (IH), is linked to nonalcoholic fatty liver disease (NAFLD).
• The precise mechanisms driving OSA-induced NAFLD are not fully understood, limiting effective therapeutic strategies.
• Ferroptosis, a form of regulated cell death, is implicated but its specific role in OSA-related NAFLD requires elucidation.

Purpose of the Study:

• To investigate the role and underlying mechanisms of ferroptosis in the development of NAFLD associated with OSA.
• To analyze clinical data, conduct cell-based experiments, and perform animal studies to understand OSA's impact on liver health.
• To identify potential therapeutic targets for mitigating NAFLD progression in OSA patients.

Main Methods:

• Analysis of liver function indicators, lipid accumulation, and ferroptosis markers in clinical and experimental models.
• Utilized RNA-sequencing, qPCR, and Western blotting to assess gene and protein expression.
• Employed gene intervention, E3 ligase prediction (UbiBrowser), and co-immunoprecipitation (co-IP) to explore molecular pathways.

Main Results:

• Elevated ferroptosis was observed in the liver tissues of patients with OSA.
• Chronic IH exacerbated NAFLD progression in mice, an effect mitigated by the ferroptosis inhibitor Fer-1.
• Macrophage-secreted IL6 upregulated MARCH3 in hepatocytes under IH, leading to GPX4 ubiquitination and degradation, thus regulating ferroptosis and lipid accumulation.

Conclusions:

• Ferroptosis plays a critical role in the pathogenesis of NAFLD induced by OSA.
• Targeting MARCH3 could be a promising therapeutic strategy to inhibit IH-induced ferroptosis and lipid accumulation, thereby preventing NAFLD progression.