Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease

作者：Yi-Huai He, Jin-Lian Jiang, Lili Ou, Yunfen Chen, Aikedaimu Abudukeremu, Guimei Chen, Weiwei Zhong, Zhigang Jiang, Nuerbiye Nuermaimaiti, Yaqun Guan · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02312-3 · 被引用次数：20 · 研究领域：Liver Disease Diagnosis and Treatment、Endoplasmic Reticulum Stress and Disease、Liver Disease and Transplantation

RelA, also known as nuclear factor kappa B p65, plays a crucial role in the pathogenesis of various liver diseases. However, the specific role of RelA in hepatocytes during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is not well understood. This study explored the relationship between impaired RelA signaling and lipid metabolism disorders in hepatocytes, and how they synergistically contribute to the advancement of MASLD. We assessed the changes, regulatory relationships, and impacts of RelA signaling and lipid metabolism remodeling on disease progression both in vitro and in vivo. During MASLD, there was a decrease in the expression of RelA and hepatocyte nuclear factor 1 alpha (HNF1α), with both factors showing mutual enhancement of each other's expression under normal conditions. This synergistic effect was absent during hepatocyte steatosis. RelA or HNF1α depletion in hepatocytes intensified MASLD symptoms, whereas overexpression of RELA or treatment with necrostatin-1 (a necroptosis inhibitor) or Z-VAD (a caspase inhibitor) significantly mitigated these effects. Mechanistically, during hepatic steatosis, altered lipid profiles exhibited lipotoxicity, inducing hepatocyte apoptosis and necroptosis, whereas endoplasmic reticulum (ER) stress triggered lipid remodeling processes similar to those observed in MASLD. RelA signaling upregulated the expression of activating transcription factor 4 and glucose-regulated protein 78, thereby all...