Sepsis is a systemic inflammatory response syndrome with high mortality and morbidity worldwide. In this study, we demonstrate that capsaicin not only suppresses inflammation in lipopolysaccharide (LPS)-induced macrophages, but also effectively inhibits endotoxemia or sepsis-related inflammation in vivo. We have designed and synthesized a series of capsaicin-based probes, which permit the profiling of the target proteins of capsaicin using activity-based protein profiling (ABPP). Among the identified protein targets, we discover that capsaicin directly binds to and inhibits PKM2 and LDHA, and further suppresses the Warburg effect in inflammatory macrophages. Moreover, capsaicin targets COX-2 and downregulates its expression in vivo and in vitro. Taken together, the present findings indicate that capsaicin alleviates the inflammation response and the Warburg effect in a TRPV1-independent manner by targeting PKM2-LDHA and COX-2 in sepsis. Thus, capsaicin may function as a novel agent for sepsis and inflammation treatment.

脓毒症是一种全身性炎症反应综合征，在全球范围内具有高死亡率和高发病率。在这项研究中，我们证明辣椒素不仅能抑制脂多糖 (LPS) 诱导的巨噬细胞炎症，而且还能有效抑制体内内毒素血症或败血症相关炎症。我们设计并合成了一系列基于辣椒素的探针，允许使用基于活性的蛋白质分析 (ABPP) 分析辣椒素的靶蛋白。在确定的蛋白质靶点中，我们发现辣椒素直接结合并抑制 PKM2 和 LDHA，并进一步抑制炎症巨噬细胞中的 Warburg 效应。此外，辣椒素靶向 COX-2 并下调其在体内和体外的表达. 总之，目前的研究结果表明，辣椒素通过靶向脓毒症中的 PKM2-LDHA 和 COX-2 以不依赖 TRPV1 的方式减轻炎症反应和 Warburg 效应。因此，辣椒素可作为治疗败血症和炎症的新型药物。