Chronic intermittent hypoxia exacerbates the progression of NAFLD via SPP1- mediated inflammatory polarization in macrophages

Fang Ying Lu; Xi Xi Chen; Mengyao Li; Ya Ru Yan; Yi Wang; Shi Qi Li; Liu Zhang; Ying Ni Lin; Jian Ping Zhou; Li Na Zhou; Qing Yun Li

doi:10.1016/j.freeradbiomed.2025.06.050

Chronic intermittent hypoxia exacerbates the progression of NAFLD via SPP1- mediated inflammatory polarization in macrophages

Free Radic Biol Med. 2025 Jun 25:S0891-5849(25)00799-3. doi: 10.1016/j.freeradbiomed.2025.06.050. Online ahead of print.

Authors

Fang Ying Lu¹, Xi Xi Chen¹, Mengyao Li¹, Ya Ru Yan¹, Yi Wang¹, Shi Qi Li¹, Liu Zhang¹, Ying Ni Lin¹, Jian Ping Zhou¹, Li Na Zhou¹, Qing Yun Li²

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai 200025, China.
² Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai 200025, China. Electronic address: liqingyun68@hotmail.com.

PMID: 40578540
DOI: 10.1016/j.freeradbiomed.2025.06.050

Abstract

Background: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), has been implicated in the development and progression of non-alcoholic fatty liver disease (NAFLD). The importance of macrophages in NAFLD pathogenesis has been well-documented, yet the impact of CIH on liver macrophages and the underlying mechanisms during NAFLD progression remain largely unclear.

Methods: In this study, we established two types of NAFLD murine models and simultaneously exposed the mice to CIH or room air condition to evaluate the impact of CIH on hepatic pathophysiology and liver macrophages status. In vitro experiments utilizing bone marrow-derived macrophages (BMDMs) were conducted to validate the CIH-induced macrophage polarization and its contribution to hepatocyte injury. Furthermore, the role of secreted phosphorylated protein 1 (SPP1) in CIH-mediated macrophage polarization was investigated.

Results: CIH exposure significantly exacerbated liver injury in both high-fat diet and methionine-choline-deficient diet induced NAFLD models, as indicated by increased hepatic inflammation and fibrosis. Further liver macrophages analysis revealed a marked increase in macrophage accumulation and a significant shift towards M1 polarization under CIH conditions during NAFLD progression. Similarly, CIH-exposed BMDMs demonstrated pronounced M1 polarization and pro-inflammatory activation, which aggravated lipid-induced hepatocyte injury. Transcriptomic analysis identified consistent upregulation of Spp1 in both CIH-exposed BMDMs and liver macrophages from NAFLD murine models. Elevated SPP1 expression was also confirmed in CIH-exposed macrophages and NAFLD liver tissues. Functional validation studies revealed that SPP1 knockdown in macrophages effectively attenuated CIH-induced M1 polarization and reduced associated inflammatory and fibrotic injury in hepatocytes.

Conclusion: CIH promotes inflammatory polarization of liver macrophages through the upregulation of SPP1, thereby exacerbating hepatocyte injury and accelerating the progression of NAFLD.

Keywords: CIH; M1 polarization; Macrophages; NAFLD; OSA; SPP1.