Ferroptosis: principles and significance in health and disease

Abstract

Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed by molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic cell death pathway in 2012, ferroptosis has emerged as a crucial mechanism in numerous physiological and pathological contexts, leading to significant therapeutic advancements across a wide range of diseases. This review summarizes the fundamental molecular mechanisms and regulatory pathways underlying ferroptosis, including both GPX4-dependent and -independent antioxidant mechanisms. Additionally, we examine the involvement of ferroptosis in various pathological conditions, including cancer, neurodegenerative diseases, sepsis, ischemia-reperfusion injury, autoimmune disorders, and metabolic disorders. Specifically, we explore the role of ferroptosis in response to chemotherapy, radiotherapy, immunotherapy, nanotherapy, and targeted therapy. Furthermore, we discuss pharmacological strategies for modulating ferroptosis and potential biomarkers for monitoring this process. Lastly, we elucidate the interplay between ferroptosis and other forms of regulated cell death. Such insights hold promise for advancing our understanding of ferroptosis in the context of human health and disease.

Keywords: Biomarker; Cancer therapy; Ferroptosis; Human disease; Immunity.

Fig. 1

Molecular mechanisms of ferroptosis. Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation and subsequent plasma membrane rupture. It can occur via two primary pathways: the extrinsic pathway, which relies on transporters such as activating TFRC or inhibiting system xc-, and the intrinsic pathway, which is enzyme-regulated, for example, by inhibiting GPX4 or AIFM2. Ferroptosis arises from an imbalance between oxidants and antioxidants, driven by abnormal expression and activity of various redox-active enzymes that either produce or neutralize free radicals and lipid oxidation products. The plasma membrane damage can be repaired by the NINJ1 protein or ESCRT-III machinery

Fig. 2

Regulation of ferroptosis. A SIGMAR1 interacts with ITPR to facilitate calcium exchange between the endoplasmic reticulum (ER) and mitochondria, promote lipid droplet catabolism, and enhance sensitivity to ferroptosis. Moreover, the PACS2, HSPA9/VDAC1 complex also mediates the transmission of ferroptosis signals from the ER to mitochondria. B CA9 inhibits ferroptosis through the AMPK pathway or by directly inducing alkalinization of intracellular pH. Additionally, HIF1A-dependent lactate accumulation inhibits ferroptosis via a pH-dependent mechanism. C Intestinal flora secretes metabolites such as IDA, CAT, or daidzein to modulate the expression of AIFM2 or GPX4 and suppress ferroptosis. D Cancer cells utilize the macropinocytosis pathway to uptake proteins like extracellular albumin to supplement cysteine and inhibit ferroptosis under conditions of system xc- inhibition. Moreover, albumin may directly inhibit lipid peroxidation

Fig. 3

The pathological significance of ferroptosis. Ferroptosis has been implicated in a variety of diseases across different organs and tissues. In cancer, for example, ferroptosis resistance contributes to tumor progression and treatment resistance, while inducing ferroptosis has emerged as a potential therapeutic strategy. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, excessive lipid peroxidation and ferroptosis have been observed in affected brain regions, suggesting a role in neuronal death. Ischemia–reperfusion injury in organs like the heart and kidney involves oxidative stress and lipid peroxidation, leading to tissue damage characteristic of ferroptosis. Understanding the mechanisms and regulation of ferroptosis in various diseases holds promise for the development of novel therapeutic interventions targeting this pathway

Fig. 4

Ferroptosis in cancer therapy. Conventional cancer treatments, such as chemotherapy, radiotherapy, immunotherapy and nanotherapy can trigger ferroptosis, halting tumor growth. However, they may also activate pathways enabling cancer cells to evade ferroptosis. Therefore, combining therapies with the inhibition of ferroptosis escape pathways can significantly improve treatment outcomes. Ferroptotic cancer cells release damage-associated molecular patterns (DAMPs), which play a dual role in either promoting or inhibiting antitumor immunity, depending on the specific type and stage of cancer

Fig. 5

Relationship between ferroptosis and immunogenic cell death. Ferroptotic cancer cells release damage-associated molecular patterns (DAMPs), expose calreticulin (CRT), and demonstrate some level of immunogenicity, resembling a form of immunogenic cell death (ICD). However, the challenges encountered in prophylactic vaccine trials and the observed immunosuppressive effects associated with increased PTGS2 and PGE2 expression, oxidized HMGB1, and phospholipid peroxidation during ferroptosis suggest that ferroptosis may not fully meet the criteria for being classified as ICD

Fig. 6

Crosstalk between ferroptosis and other RCD pathways. Many proteins or mental ions are multifunctional, tandem with ferroptosis and alkaliptosis, cuproptosis, pyroptosis and apoptosis