Supplemental material

Dairy cows with ketosis often experience liver dysfunction, characterized by hepatocellular injury and increased hepatic inflammation response. However, the underlying mechanism of these pathogenic events remains unclear. Necroptosis, a form of programmed cell death that promotes organ inflammatory injury, plays a critical role in the pathogenesis of liver diseases. In this study, we confirmed the occurrence of necroptosis in the liver of dairy cows with ketosis. We found that tumor necrosis factor-alpha (TNF-α), as a ketosis-associated inflammatory cytokine, induced necroptosis in bovine hepatocytes. Furthermore, inhibiting necroptosis via the RIPK1 kinase inhibitor Nec-1 and RIPK3 kinase inhibitor GSK-872 alleviated TNF-α-induced cellular damage. These findings suggest that targeting necroptosis could be a potential therapeutic strategy to mitigate hepatic damage in dairy cows with ketosis.

患有酮病的奶牛常出现肝功能障碍，其特征为肝细胞损伤及肝脏炎症反应加剧。然而，此类致病事件的潜在分子机制仍未明确。细胞坏死性凋亡（Necroptosis）是一种可促进器官炎症损伤的程序性细胞死亡形式，在肝脏疾病的发病机制中发挥关键作用。本研究证实了酮病奶牛肝脏中存在细胞坏死性凋亡现象。研究发现，作为与酮病相关的炎症细胞因子，肿瘤坏死因子-α（tumor necrosis factor-alpha, TNF-α）可诱导牛肝细胞发生坏死性凋亡。此外，通过RIPK1激酶抑制剂Nec-1及RIPK3激酶抑制剂GSK-872抑制细胞坏死性凋亡，可缓解TNF-α介导的细胞损伤。上述研究结果表明，靶向调控细胞坏死性凋亡或可作为缓解酮病奶牛肝脏损伤的潜在治疗策略。