Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication caused by inflammation, but how it is initiated is still unclear. Several studies have shown that extracellular high mobility group box 1 (HMGB1), an important cytokine triggering inflammation, is overexpressed during the pathogenesis of SIMD, but the underlying mechanism regarding its overexpression is still unknown. Herein, we discovered that CUL4A (cullin 4A) assembled an E3 ligase complex with RBX1 (ring-box 1), DDB1 (DNA damage-binding protein 1), and DCAF8 (DDB1 and CUL4 associated factor 8), termed CRL4A^DCAF8, which ubiquitinated and degraded NcoR1 (nuclear receptor corepressor 1) in an LPS-induced SIMD mouse model. The degradation of NcoR1 failed to form a complex with the SP1 transcription factor, leading to the upregulation of HMGB1. Mature HMGB1 functioned as an effector to induce the expression of proinflammatory cytokines, causing inflammation and resulting in SIMD pathology. Using an in vitro AlphaScreen technology, we identified three small molecules that could inhibit the CUL4A-RBX1 interaction. Of them, PSSM0332 showed the strongest ability to inhibit the ubiquitination of NcoR1, and its administration in SIMD mice exhibited promising effects on decreasing the inflammatory response. Collectively, our results reveal that the CRL4A^DCAF8 E3 ligase is critical for the initiation of SIMD by regulating the expression of HMGB1 and proinflammatory cytokines. Our results suggest that PSSM0332 is a promising candidate to inhibit the inflammatory response in the pathogenesis of SIMD, which will provide a new option for the therapy of SIMD.

中文翻译：

---

小分子 PSSM0332 解离 CRL4ADCAF8 E3 连接酶复合物以减少 NcoR1 的泛素化并抑制小鼠败血症诱导的心肌功能障碍模型中的炎症反应

脓毒症诱发的心肌功能障碍 (SIMD) 是一种由炎症引起的危及生命的并发症，但它是如何引发的仍不清楚。多项研究表明，细胞外高迁移率组框 1 (HMGB1) 是一种重要的炎症触发细胞因子，在 SIMD 的发病过程中过度表达，但其过度表达的潜在机制仍不清楚。在这里，我们发现 CUL4A (cullin 4A) 与 RBX1（环盒 1）、DDB1（DNA 损伤结合蛋白 1）和 DCAF8（DDB1 和 CUL4 相关因子 8）组装了一个 E3 连接酶复合物，称为 CRL4A ^DCAF8，它在 LPS 诱导的 SIMD 小鼠模型中泛素化和降解 NcoR1（核受体辅阻遏物 1）。NcoR1的降解未能与SP1转录因子形成复合物，导致HMGB1上调。成熟的 HMGB1 作为一种效应器发挥作用，诱导促炎细胞因子的表达，引起炎症并导致 SIMD 病理。使用体外AlphaScreen 技术，我们确定了三种可以抑制 CUL4A-RBX1 相互作用的小分子。其中，PSSM0332 显示出最强的抑制 NcoR1 泛素化的能力，并且其在 SIMD 小鼠中的给药在降低炎症反应方面表现出良好的效果。总的来说，我们的结果表明 CRL4A ^DCAF8E3 连接酶通过调节HMGB1和促炎细胞因子的表达对 SIMD 的启动至关重要。我们的研究结果表明，PSSM0332是抑制SIMD发病机制中炎症反应的有希望的候选药物，这将为SIMD的治疗提供新的选择。