脓毒性心肌损伤是最危及生命的器官功能障碍之一。基于γ-分泌酶的方法已被发展为多种疾病管理的潜在策略。然而，γ-分泌酶抑制剂在脓毒性心肌损伤中的作用尚不清楚。本研究旨在调查γ-分泌酶抑制剂在脓毒性心肌损伤中的效应，并揭示其机制。通过腹腔注射脂多糖（LPS）建立小鼠脓毒性心肌损伤模型，并在该模型中应用γ-分泌酶抑制剂MW167。采用RNA测序分析和进一步的生物信息学分析，筛选出LPS和LPS+MW167小鼠之间的差异表达基因（DEGs）和潜在富集途径。使用苏木精-伊红染色进行病理学检查。在H9C2细胞中使用SD-1029来阻断JAK2/STAT3信号通路，通过Western blot分析定量JAK2/STAT3相关蛋白。LPS诱导心肌损伤伴随明显的炎症浸润和更多凋亡细胞。转录组测序筛选出36个DEGs，并且生物信息学分析发现JAK2/STAT3信号通路富集显著。进一步的体外实验表明，γ-分泌酶抑制剂MW167激活了JAK2/STAT3通路。此外，MW167恢复了细胞活力，降低了心肌损伤标志物包括心肌肌钙蛋白I（cTnI）和脑利钠肽（BNP），抑制了促炎细胞因子如白介素（IL）-1β和肿瘤坏死因子-α（TNF-α），减少了一氧化氮（NO）的释放，环氧合酶-2（COX2）和可诱导型一氧化氮合酶（iNOS）。SD-1029的应用在γ-分泌酶抑制剂处理的心肌细胞中反向恶化了LPS诱导的心肌损伤和炎症反应。结果表明，γ-分泌酶抑制剂通过激活JAK2/STAT3信号通路缓解了脓毒性心肌损伤，并为脓毒性心肌损伤提供了新的治疗方向。© 2023 Wiley Periodicals LLC.

Septic myocardial injury is one of the most life-threatening organ dysfunction. The γ-secretase-based approaches have been developed as potential strategies for diverse diseases management. Unfortunately, the role of γ-secretase inhibitor in septic myocardial injury is unclarified. The present study aims to investigate the effect of γ-secretase inhibitor in septic myocardial injury and reveal its mechanism.The mouse model of septic myocardial injury was established by intraperitoneally injection of lipopolysaccharide (LPS), and γ-secretase inhibitor MW167 was applied in this model. RNA-sequencing analysis and further bioinformatics analyses were used to screen differential expressed genes (DEGs) and potentially enriched pathways between LPS and LPS + MW167 mice. Pathological examination was performed using haematoxylin and eosin (HE) staining. SD-1029 was used to block JAK2/STAT3 signaling in H9C2 cells and western blot analysis quantified JAK2/STAT3-related proteins.LPS induced myocardial injury accompanied with significant inflammatory infiltration and more apoptotic cells. Transcriptome sequencing screened 36 DEGs and bioinformatics identified JAK2/STAT3 signaling pathway was significantly enriched. Further in vitro experiments showed that γ-secretase inhibitor MW167 activated JAK2/STAT3 pathway. Additionally, MW167 restored cell viability, decreased myocardial injury markers including cardiac troponin I (cTnI) and brain natriuretic peptide (BNP), inhibited pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) and reduced nitric oxide (NO), cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) release. Application of SD-1029 reversely deteriorated LPS-induced myocardial injury and inflammatory response in γ-secretase inhibitor-treated myocardial cells.The results demonstrate that γ-secretase inhibitor alleviates septic myocardial injury via activating JAK2/STAT3 signaling, and provide novel therapeutic direction for septic myocardial injury.© 2023 Wiley Periodicals LLC.