Sepsis is a critical condition characterized by a systemic inflammatory response to infection, often leading to severe vascular dysfunction and high mortality. One of the hallmarks of vascular dysfunction in sepsis is increased vascular permeability and the loss of pericytes, which are essential for maintaining vascular integrity. Despite the significance of pericyte loss in sepsis, the primary type of cell death responsible and the underlying molecular mechanisms remain incompletely understood. This study aims to elucidate these mechanisms by focusing on ferroptosis, a form of programmed cell death, and its regulation through the Hippo/ACSL4 axis. Our research confirmed significant pericyte loss in patients with sepsis. Through advanced single-cell analysis and proteomics, ferroptosis was identified as a key differentiating cell death type between sepsis and sham samples. Further metabolomics analysis revealed that Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) plays a pivotal role in the ferroptosis of pericytes during sepsis. In vitro experiments demonstrated that downregulation of ACSL4 effectively reduced lipopolysaccharide (LPS)-induced lipid peroxidation, restored pericyte viability, and improved endothelial permeability. In vivo studies with pericyte-specific ACSL4 knockout mice showed a marked decrease in pericyte loss and enhanced vascular barrier function following sepsis induction. To translate these findings into potential therapeutic strategies, we developed pericyte-targeting liposomes encapsulating ACSL4 shRNA adenovirus. These liposomes successfully restored pulmonary vascular barrier function and significantly reduced pericyte loss in septic conditions. The results of this study underscore the crucial role of ACSL4 in mediating ferroptosis in pericytes and highlight the therapeutic potential of targeting ACSL4 to mitigate vascular dysfunction in sepsis.

中文翻译：

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Hippo/ACSL4 轴在铁死亡诱导的脓毒症周细胞丢失和血管功能障碍中的作用


脓毒症是一种危重疾病，其特征是对感染的全身炎症反应，通常会导致严重的血管功能障碍和高死亡率。脓毒症中血管功能障碍的标志之一是血管通透性增加和周细胞丢失，这对维持血管完整性至关重要。尽管脓毒症中周细胞丢失很重要，但导致细胞死亡的主要类型和潜在的分子机制仍不完全清楚。本研究旨在通过关注铁死亡（一种程序性细胞死亡形式）及其通过 Hippo/ACSL4 轴的调节来阐明这些机制。我们的研究证实脓毒症患者存在显著的周细胞丢失。通过先进的单细胞分析和蛋白质组学，铁死亡被确定为区分脓毒症和假样本之间细胞死亡类型的关键。进一步的代谢组学分析显示，酰基辅酶 A 合成酶长链家族成员 4 （ACSL4） 在脓毒症期间周细胞的铁死亡中起关键作用。体外实验表明，下调 ACSL4 可有效降低脂多糖 （LPS） 诱导的脂质过氧化，恢复周细胞活力，提高内皮通透性。对周细胞特异性 ACSL4 敲除小鼠的体内研究表明，脓毒症诱导后周细胞丢失显著减少，血管屏障功能增强。为了将这些发现转化为潜在的治疗策略，我们开发了封装 ACSL4 shRNA 腺病毒的周细胞靶向脂质体。这些脂质体成功地恢复了肺血管屏障功能，并显着减少了脓毒症条件下的周细胞损失。 本研究的结果强调了 ACSL4 在介导周细胞铁死亡中的关键作用，并强调了靶向 ACSL4 以减轻脓毒症血管功能障碍的治疗潜力。