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Targeting ATF4-DDIT4/TXNIP induced mitochondrial dysfunction and ferroptosis: ISRIB as novel therapy for septic
Yiting Chen1,2, Xueping Feng2,3, Zeyu Li1
1Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
Introduction:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Sepsis-induced cardiomyopathy (SIC) progression is driven by DDIT4/TXNIP-mediated ferroptosis, regulated by ATF4. The inhibitor ISRIB effectively treats SIC by targeting ATF4, reducing ferroptosis and improving cardiac function.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Sepsis Pathophysiology
Background:
- Sepsis-induced cardiomyopathy (SIC) presents a significant clinical challenge with high mortality despite early reversibility.
- The precise biological mechanisms underlying SIC progression remain largely unknown, necessitating further investigation.
Purpose of the Study:
- To elucidate the molecular mechanisms driving sepsis-induced cardiomyopathy.
- To identify novel therapeutic targets and intervention strategies for SIC.
Main Methods:
- Investigated the DDIT4/TXNIP interaction and its role in SIC using co-immunoprecipitation and in vitro/vivo models.
- Determined the mechanism of SIC cell death via ferroptosis using PCR chip, Western blot, immunofluorescence, and flow cytometry.
- Evaluated the therapeutic potential of ISRIB, an ATF4 inhibitor, in a mouse model of SIC.
Main Results:
- DDIT4 exacerbates SIC by promoting inflammatory infiltration and cardiac dysfunction through the TXNIP pathway.
- The DDIT4/TXNIP axis drives SIC progression via ferroptosis, with ATF4 identified as a key upstream regulator.
- ISRIB significantly reduced inflammation and ferroptosis in SIC, improving cardiac function and prognosis in mice.
Conclusions:
- The DDIT4/TXNIP-mediated ferroptosis pathway, regulated by ATF4, exacerbates SIC by increasing inflammation and impairing cardiac function.
- Targeting ATF4 with the small-molecule inhibitor ISRIB offers a promising therapeutic strategy to attenuate ferroptosis and protect cardiac function in SIC.
- This study identifies a novel therapeutic target and intervention for the clinical management of sepsis-induced cardiomyopathy.
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