Chen Yiting, Feng Xueping, Li Zeyu, Wang Xinrun, Xiong Wei, Liu Jie, Wang Guotao, Xu Wenye, Jin Rui, Zhang Lina, Qian Zhaoxin
Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
J Transl Med. 2025 Aug 19;23(1):938. doi: 10.1186/s12967-025-06939-9.
Sepsis-induced cardiomyopathy (SIC) is a reversible lesion in the early clinical stage, but often induces a high mortality rate in the late stage, and its specific mechanism is unknown. Thus, in-depth exploration of the biological progression mechanism of SIC plays a crucial role.
Through co-immunoprecipitation and molecular biological experiments, the functional interaction relationship between DDIT4 and TXNIP was clarified, and the effect of DDIT4/TXNIP on the progression of SIC was investigated both in vitro/vivo. Additionally, the mechanism of SIC cell death mediated by DDIT4/TXNIP was determined through PCR chip technology, Western blot, immunofluorescence, flow cytometry and in-vivo SIC model experiments. Finally, leveraging the upstream transcription factor ATF4 as a target for the DDIT4/TXNIP pathway, a novel application and translational study of its small-molecule inhibitor ISRIB in SIC was developed.
Firstly, in-vitro/vivo experiments demonstrated that DDIT4 exacerbates inflammatory infiltration and cardiac dysfunction in SIC via the TXNIP pathway. Mechanistically, the DDIT4/TXNIP axis promotes SIC progression through ferroptosis mechanisms. Furthermore, our study identified ATF4, an upstream transcription factor of DDIT4/TXNIP, as a key regulatory switch for this biological mechanism. Finally, this study confirmed that ISRIB, a small-molecule inhibitor of ATF4, significantly suppresses inflammation and ferroptosis mediated by DDIT4/TXNIP, thereby markedly improving cardiac function and prognosis in SIC mice.
This study revealed that the DDIT4/TXNIP-mediated ferroptosis mechanism exacerbates the inflammatory release and cardiac function decline in SIC. It also clarified that this biological effect is regulated by ATF4. Moreover, it was proposed that the inhibitor ISRIB, which targets ATF4, can significantly attenuate ferroptosis in SIC, while concurrently protecting cardiac function. This finding provides a brand-new therapeutic target and intervention agent for the clinical treatment of SIC.
脓毒症诱导的心肌病（SIC）在临床早期是一种可逆性病变，但在晚期常导致高死亡率，其具体机制尚不清楚。因此，深入探究SIC的生物学进展机制至关重要。
通过免疫共沉淀和分子生物学实验，阐明DDIT4与TXNIP之间的功能相互作用关系，并在体外/体内研究DDIT4/TXNIP对SIC进展的影响。此外，通过PCR芯片技术、蛋白质免疫印迹法、免疫荧光法、流式细胞术和体内SIC模型实验，确定DDIT4/TXNIP介导的SIC细胞死亡机制。最后，以上游转录因子ATF4作为DDIT4/TXNIP通路的靶点，开展其小分子抑制剂ISRIB在SIC中的新应用及转化研究。
首先，体外/体内实验表明，DDIT4通过TXNIP途径加剧SIC中的炎症浸润和心脏功能障碍。从机制上讲，DDIT4/TXNIP轴通过铁死亡机制促进SIC进展。此外，我们的研究确定DDIT4/TXNIP的上游转录因子ATF4是这一生物学机制的关键调节开关。最后，本研究证实，ATF4的小分子抑制剂ISRIB可显著抑制DDIT4/TXNIP介导的炎症和铁死亡，从而显著改善SIC小鼠的心脏功能和预后。
本研究揭示了DDIT4/TXNIP介导的铁死亡机制加剧了SIC中的炎症释放和心脏功能下降。还阐明了这种生物学效应受ATF4调节。此外，提出靶向ATF4的抑制剂ISRIB可显著减轻SIC中的铁死亡，同时保护心脏功能。这一发现为SIC的临床治疗提供了全新的治疗靶点和干预药物。
