Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential

Abstract

Sepsis is a common critical illness in the Intensive care unit(ICU) and its management and treatment has always been a major challenge in critical care medicine. The dysregulated host response to infection, causing systemic multi-organ and multi-system damage is the main pathogenesis. Notably, intense stress during sepsis can lead to metabolic disturbances of ions, lipids and energy in the organism. Ferroptosis is an iron-dependent, non-apoptotic cell death distinguished by a disruption of iron metabolism and iron-dependent accumulation of lipid peroxides. Mounting researches have established that ferroptosis has an essential part in anti-inflammatory and sepsis, and drugs targeting ferroptosis-related molecules, such as ferroptosis inhibitors, are gradually proving their effectiveness in sepsis. This paper summarizes and reviews the pathogenesis of ferroptosis, its regulatory network, and its vital involvement in the initiation of sepsis and related organ damage, and finally discusses the possible target drugs provided by the above mechanisms, describes the dilemmas as well as the outlook, in the hope of finding more links between ferroptosis and sepsis and providing new perspectives for the future treatment of sepsis.

Opportunities and challenges related to ferroptosis in glioma and neuroblastoma

“…GSH is not required as a cofactor for this process, nor does this process depend on GPX4. As a result, in contrast to GPX4, FSP1 may be regarded as a ferroptosis inhibitor, and the expression of FSP1 confirms the sensitivity of cells to ferroptosis (8,10,11).…”

“…Upregulating or inhibiting these antioxidant systems to regulate ferroptosis can impact the development of various diseases. Moreover, studies have identified various drugs and molecules as inducers of ferroptosis that act by restricting Xc system activity (8,9).…”

“…The GTP cyclohydrolase 1 (GCH1)-BH4 axis controls BH4 synthesis and reduces intracellular CoQ and ROS accumulation, thereby leading to ferroptosis inhibition. In addition, GCH1/BH4 exerts a selective inhibitory impact on nuclear receptor coactivator 4 (NCOA4)-mediated ferritin autophagy and affects iron metabolism (8,35). This provides a new direction for ferroptosis research in glioma.…”

Exploring Dysregulated Ferroptosis-Related Genes in Septic Myocardial Injury Based on Human Heart Transcriptomes: Evidence and New Insights

“…13,14 There is evidence of iron homeostasis disorder in both circulating blood and organ tissues of septic patients, which has been found to be related to the clinical prognosis. [15][16][17] Since ferroportin is the only known iron exporter in vertebrate cells, cellular iron overload is susceptible to occur when iron homeostasis is disordered. 14 Iron is an important trace element involved in multiple biological processes such as DNA synthesis and energy production.…”

“…13 Ferroptosis is a form of programmed cell death driven by irondependent lipid peroxidation, which has unique morphological, genetic, and biochemical characteristics. 17,18 Recent studies have reported ferroptosis in both in vivo and in vitro SMI models, and inhibition of ferroptosis by small molecule compounds has been found to be protective in SMI models. [19][20][21] Despite increased research focus on the role of ferroptosis in SMI, the current understanding of its molecular biology is still scattered and unclear, further in-depth exploration is necessary and urgent, which may lead to promising targets for diagnosis and treatment.…”