Chronic hypoxia induces liver injury via PKCδ/ASMase-driven ceramide accumulation and endoplasmic reticulum stress in rats.

BACKGROUND AND AIM: Chronic continuous hypoxia imposes a huge physiological burden and impacts human health. The liver is critical for maintaining whole-body homeostasis. Although accumulating evidence has linked hypoxia to liver damage, the underlying mechanisms are poorly understood. This study investigated the effects of chronic continuous hypoxia on the liver and the underlying mechanisms. METHODS: Rats were exposed to 10% O₂ for 6 weeks. Treatment groups received the acid sphingomyelinase (ASMase) inhibitor desipramine (Des), the protein kinase C delta (PKCδ) inhibitor rottlerin, or the endoplasmic reticulum stress (ERS) inhibitor 4-Phenylbutyric Acid (4-PBA). The analyses included liver histopathology (Hematoxylin and Eosin staining), ultrastructural observations, serum liver function indicators, serum and hepatic lipidomics, enzyme activities, and ERS markers. RESULTS: Chronic hypoxia altered liver and serum lipid profiles, with hepatic ceramide (Cer) levels showing the most significant increase. Hypoxia increased hepatic Cer levels via ASMase activation, and the ASMase inhibitor Des reduced the serum levels of liver function indicators and ameliorated hepatic histological abnormalities in hypoxic rats. Rottlerin inhibited ASMase activity and ameliorated hypoxia-induced liver injury. Des blocked hypoxia-induced hepatic ERS, and 4-PBA alleviated hypoxic liver injury. CONCLUSION: Chronic continuous hypoxia caused liver damage, partially through Cer-mediated ERS via activation of the PKCδ/ASMase axis. Therefore, Cer might be a promising diagnostic biomarker for liver injury in high-altitude residents and patients with cardiopulmonary diseases. Targeting the PKCδ/ASMase/Cer axis represents a potential therapeutic strategy for mitigating hypoxic liver injury. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12944-025-02761-w.