The Expanding Horizon of Ferroptosis: Mechanisms, Disease Relevance and Therapeutics


Ferroptosis is a regulated form of cell death characterized by its dependency on iron and distinguished by the accumulation of lipid peroxides, which distinguishes it from other forms of cell death such as apoptosis, necrosis, and autophagy. Since its formal identification and naming by Dixon et al. in 2012, the understanding of ferroptosis has significantly advanced, revealing intricate mechanisms and its implications for a variety of diseases.

Mechanistic Insights into Ferroptosis

Ferroptosis is driven by complex biological pathways involving iron metabolism, lipid peroxidation, and amino acid metabolism. The suppression of the system Xc-, a cystine/glutamate antiporter, and the inactivation of glutathione peroxidase 4 (GPX4) are pivotal in the induction of ferroptosis. System Xc- plays a crucial role in maintaining cellular redox balance by facilitating the uptake of cystine, which is converted into cysteine, a precursor for glutathione (GSH), an essential antioxidant.

The inhibition of GPX4, a key enzyme that converts toxic lipid peroxides into non-toxic lipid alcohols using GSH, leads to the accumulation of lipid peroxides, a hallmark of ferroptosis. Furthermore, mitochondrial voltage-dependent anion channels (VDACs) and the tumor suppressor protein P53 have been implicated in the regulation of ferroptosis, highlighting the complexity of its regulatory mechanisms​​​​.

Lipid peroxidation is a critical event in ferroptosis, mediated by both enzymatic and non-enzymatic mechanisms. Polyunsaturated fatty acids (PUFAs) in cellular membranes are particularly susceptible to peroxidation, leading to membrane damage and cell death. Iron metabolism plays a central role in ferroptosis by facilitating the Fenton reaction, which generates reactive oxygen species (ROS) and promotes lipid peroxidation. The regulation of iron homeostasis, including iron uptake, storage, and export, is thus crucial in the modulation of ferroptosis​​.

Ferroptosis in Disease and Therapy

The significance of ferroptosis extends beyond a mere cellular death pathway; it has profound implications for various diseases, including cancer, neurodegeneration, and organ damage. By understanding the mechanisms underlying ferroptosis, researchers have identified potential therapeutic targets for conditions where ferroptosis may play a pathogenic role. For instance, the manipulation of ferroptosis has emerged as a promising strategy in cancer therapy, where the induction of ferroptosis in cancer cells can lead to their selective elimination. Conversely, inhibiting ferroptosis may offer therapeutic benefits in diseases characterized by unwanted cell death, such as neurodegenerative disorders and ischemia-reperfusion injuries​​​​.

The ongoing research into ferroptosis is uncovering new regulators, signaling pathways, and interactions with other forms of cell death, broadening our understanding of cellular death mechanisms and their implications for health and disease. As the field advances, the development of novel diagnostic markers and therapeutic agents targeting ferroptosis holds the promise for innovative treatments for a wide range of diseases.

The Mechanisms of Ferroptosis: A Detailed Analysis of Regulatory Pathways

Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a significant phenomenon in various physiological and pathological processes. Understanding the intricate regulatory mechanisms governing ferroptosis is crucial for developing potential therapeutic strategies targeting this process. In this article, we delve into the three primary categories of regulatory mechanisms: iron metabolism, glutathione peroxidase 4 (GPX4), and lipid metabolism. Additionally, we explore the role of Ferroptosis Suppressor Protein 1 (FSP1), particularly focusing on its involvement in the FSP1-CoQ10-NAD(P)H pathway.

Regulation by Iron Metabolism

Iron, a vital element in cellular metabolism, plays a central role in ferroptosis. Intracellular iron levels are tightly regulated by proteins such as ferritin, transferrin, and iron regulatory proteins (IRPs). Disruption of iron homeostasis can lead to excessive iron accumulation, promoting lipid peroxidation and ferroptotic cell death. Recent studies have elucidated the intricate interplay between iron metabolism and ferroptosis, highlighting potential targets for therapeutic intervention.

Regulation by Glutathione Peroxidase 4 (GPX4)

GPX4, a selenoprotein with peroxidase activity, is a key regulator of ferroptosis. By catalyzing the reduction of lipid hydroperoxides to their corresponding alcohols, GPX4 prevents the accumulation of lipid peroxides and protects cells from ferroptotic death. However, GPX4 activity can be inhibited by various factors, including depletion of its cofactor glutathione (GSH) or direct inhibition by small molecules such as RSL3. Understanding the regulatory mechanisms governing GPX4 activity is essential for modulating ferroptosis in disease states.

Regulation by Lipid Metabolism

Lipid metabolism plays a crucial role in ferroptosis susceptibility. Polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA) and adrenic acid (AdA), are highly susceptible to peroxidation, leading to membrane damage and cell death. Enzymes involved in lipid metabolism, such as lipoxygenases (LOXs) and acyl-CoA synthetase long-chain family member 4 (ACSL4), regulate the levels of lipid peroxides and influence ferroptotic cell death. Targeting lipid metabolism pathways represents a promising approach for modulating ferroptosis in various pathological conditions.

The FSP1-CoQ10-NAD(P)H Pathway

FSP1, also known as apoptosis-inducing factor mitochondria-associated 2 (AIFM2), has recently emerged as a critical regulator of ferroptosis. Through its anti-ferroptotic activity, FSP1 protects cells from lipid peroxidation and ferroptotic cell death. The FSP1-CoQ10-NAD(P)H pathway represents an independent system that interacts with GPX4 and GSH to inhibit phospholipid peroxidation and ferroptosis. FSP1 catalyzes the regeneration of Coenzyme Q10 (CoQ10) using NAD(P)H, thereby suppressing lipid oxidation and inhibiting ferroptosis. These findings underscore the therapeutic potential of targeting the FSP1-CoQ10-NAD(P)H pathway for the treatment of diseases characterized by dysregulated ferroptosis.

The Significance of the BH4-DHFR Pathway in Ferroptosis Regulation

In the realm of cellular biology, the intricate mechanisms underlying ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, continue to captivate researchers. Amidst the labyrinth of pathways governing this phenomenon, the BH4-DHFR pathway emerges as a compelling protagonist, wielding significant influence over ferroptotic cell fate. Delving into the depths of molecular intricacies, Kraft et al. embarked on a groundbreaking exploration, scrutinizing a cohort of genes implicated in countering ferroptotic demise. Within this constellation of genes, GTP cyclohydrolase-1 (GCH1) and its metabolic derivatives, tetrahydrobiopterin/dihydrobiopterin (BH4/BH2), beckoned attention, igniting a quest for understanding their role in ferroptosis resistance.

The saga unfolds with the synthesis of BH4/BH2 by GCH1-expressing cells, catalyzing a cascade of events that intricately remodel lipids while curbing the relentless march of ferroptosis. This transformative process instigates lipid remodeling, a pivotal maneuver orchestrated by BH4/BH2, crucial for shielding cellular constituents from pernicious oxidative assault. The crux of this protective mechanism lies in BH4’s prowess as a radical-trapping antioxidant, a guardian angel tasked with safeguarding lipids from the clutches of peroxidation.

The narrative gains momentum as the GCH1-BH4-phospholipid axis emerges as a linchpin in the labyrinthine landscape of ferroptosis regulation. Through meticulous orchestration, this axis assumes the mantle of a major regulatory pathway, dictating the delicate balance between cellular demise and survival. Central to its mandate is the preservation of phospholipids adorned with two polyunsaturated fatty acyl tails, a feat accomplished through selective prevention of their depletion. This strategic intervention not only averts the precipitous decline of phospholipids but also augments the arsenal against ferroptosis by bolstering the levels of Coenzyme Q10 (CoQ10), a vital cog in the cellular machinery.

The enigma deepens as the GCH1-BH4-phospholipid axis unveils its modus operandi, offering a glimpse into its autonomy from the canonical GPX4/glutathione system. In a paradigm-shifting revelation, this pathway transcends the confines of conventional wisdom, charting a course independent of established paradigms. Its efficacy in thwarting ferroptotic onslaught underscores its indispensability, redefining the boundaries of cellular resilience in the face of oxidative adversity.

As the chronicles of ferroptosis continue to unfold, the significance of the BH4-DHFR pathway assumes newfound prominence. Its intricate interplay with cellular dynamics not only unveils a hitherto uncharted realm of regulatory networks but also beckons forth a deeper understanding of ferroptosis and its implications in physiological and pathological contexts. In the relentless pursuit of elucidating nature’s intricate tapestry, the BH4-DHFR pathway stands as a beacon of hope, illuminating the path toward unraveling the mysteries of cellular fate.

Deciphering the Intricacies of the P53 Pathway in Ferroptosis Regulation

The P53 pathway stands as a cornerstone in cellular homeostasis, orchestrating a myriad of processes crucial for maintaining cellular integrity. One of its profound roles lies in its intricate involvement in regulating ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. Through a series of transcription-dependent and -independent mechanisms, P53 exerts both positive and negative regulatory effects on ferroptosis, thereby exerting significant influence over cellular fate.

Research conducted by Jiang et al. shed light on the multifaceted role of P53 in ferroptosis. Activation of P53 was found to significantly suppress the antioxidant capacity of cells, leading to increased lipid reactive oxygen species (ROS) and subsequent cell death. Notably, P53 was shown to inhibit cystine uptake by suppressing the expression of SLC7A11, a pivotal component of the cystine/glutamate antiporter, thus sensitizing cells to ferroptosis. Furthermore, P53’s inhibitory effects on GPX4 activity further potentiate ferroptotic cell death.

Xenotransplantation models have provided insights into the complex interplay between P53 and ferroptosis. It was elucidated that P53 indirectly activates SLC7A11 function by transcriptionally inhibiting arachidonate lipoxygenase 12 (ALOX12), thereby promoting ALOX12-dependent ferroptosis under lipid ROS stress. Additionally, the P53-SAT1-ALOX15 pathway has emerged as a crucial regulator of ferroptosis, underscoring the diverse molecular mechanisms orchestrated by P53 in this process.

Moreover, P53’s impact on glutamine metabolism further underscores its pivotal role in ferroptosis regulation. Specific P53 variants, such as the Ser47 variant, have been implicated in attenuating P53’s ability to transactivate target proteins, including glutaminase 2 (GLS2), thereby predisposing cells to ferroptotic cell death. However, contrasting findings by Tarangelo et al. suggest a nuanced role for P53 in ferroptosis regulation, wherein P53 was shown to suppress cell sensitivity to ferroptosis through the involvement of the P53-P21 axis.

Interestingly, the expression of P53 has been correlated with suppressed iron deposition in colorectal cancer cells, further highlighting its potential as a key regulator of ferroptosis in cancer contexts. Nevertheless, despite significant strides in understanding the intricate crosstalk between P53 and ferroptosis, further elucidation of specific mechanisms underlying this relationship remains imperative.

The Complexities of Iron Metabolism Pathway: Implications for Cellular Homeostasis and Ferroptosis Regulation

Iron, an essential micronutrient crucial for various cellular functions, plays a pivotal role in numerous physiological processes. Its metabolism is tightly regulated to maintain cellular homeostasis and prevent oxidative damage. Understanding the intricate pathways involved in iron metabolism is paramount for elucidating its implications in health and disease.

Iron exists predominantly in two oxidation states within the body: divalent iron (Fe2+) and trivalent iron (Fe3+). The metabolism of iron begins with its absorption from dietary sources. Non-heme iron, predominantly present in the Fe3+ form in food, requires reduction to Fe2+ for absorption in the intestines. This reduction process is facilitated by various enzymes, and once reduced, Fe3+ binds to transferrin (TF) in the serum. Transferrin receptor 1 (TFR1) on the cell membrane recognizes and internalizes the Fe3+-transferrin complex via endocytosis. Within the cell, Fe3+ is further reduced to Fe2+ by divalent metal ion transporter 1 (DMT1) or zinc-iron regulatory protein family 8/14 (ZIP8/14), allowing its incorporation into the labile iron pool (LIP).

Maintaining cellular iron homeostasis is crucial, as dysregulation can lead to oxidative stress and cell damage. The efflux of excess intracellular iron is mediated by solute carrier family 40 member 1 (SLC40A1), also known as ferroportin1 (FPN). Ferroportin1 transports Fe2+ out of the cell into the extracellular space, where it may undergo re-oxidation to Fe3+ by ferroxidases. This tightly regulated iron cycle ensures that cellular iron levels are balanced and prevents the accumulation of toxic levels of free iron.

Several proteins and regulatory factors modulate iron metabolism to maintain cellular homeostasis. Heat shock protein β-1 (HSPB1) has been identified as a regulator of intracellular iron concentrations by inhibiting TFR1 expression. Overexpression of HSPB1 has been shown to suppress ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. Additionally, the iron-storage protein ferritin, composed of ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1) subunits, sequesters excess iron within cells. The expression of iron response element-binding protein 2 (IREB2), a transcriptional factor involved in iron metabolism regulation, increases ferritin expression, thereby reducing ferrous ion concentrations and lipid reactive oxygen species production.

Furthermore, heme oxygenase-1 (HO-1), an enzyme responsible for heme degradation, has been implicated in promoting ferroptosis by releasing iron from heme. This intricate interplay between ferritin regulation, iron metabolism, and cellular responses highlights the multifaceted nature of iron homeostasis and its significance in governing cell fate.

The Interplay Between Lipid Metabolism and Ferroptosis: Insights into Cellular Mechanisms and Therapeutic Implications

Lipid metabolism pathway Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, stands at the intersection of lipid metabolism and cell fate determination. This intricate relationship underscores the importance of understanding the molecular mechanisms driving ferroptosis and its implications in various physiological and pathological contexts.

One of the central players in ferroptosis is the dysregulation of lipid metabolism, particularly the imbalance in lipid homeostasis leading to the accumulation of iron-dependent lipid reactive oxygen species (ROS). Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), are highly susceptible to peroxidation, making them critical components in ferroptotic pathways. Enzymatic or non-enzymatic oxidation of PUFAs generates lipid hydroperoxides, initiating a cascade of events culminating in ferroptotic cell death.

Key phospholipids implicated in ferroptosis include phosphatidylethanolamine (PE) containing AA or its metabolic product, adrenic acid. Acyl-CoA synthetase long-chain family member 4 (ACSL4) and phospholipid choline acyltransferase 3 (LPCAT3) play crucial roles in PE biosynthesis and remodeling, facilitating the activation of PUFAs and modulating the transmembrane properties of polyunsaturated fatty acids. The upregulation of ACSL4 enhances cellular sensitivity to ferroptosis-inducing compounds, while suppression of ACSL4 and LPCAT3 expression reduces intracellular lipid peroxide accumulation, mitigating ferroptotic cell death. Furthermore, PUFA-PE can serve as substrates for lipoxygenase (LOX), further propagating lipid ROS-mediated cell damage and promoting ferroptosis.

In addition to lipid metabolism, the interplay between autophagy and ferroptosis adds another layer of complexity to cell fate regulation. Autophagy, a cellular degradation process crucial for maintaining cellular homeostasis, can either promote cell survival or contribute to cell death, depending on the context. Excessive autophagy, particularly selective autophagy, has been implicated in ferroptosis by promoting iron accumulation and lipid peroxidation.

The ATG5-ATG7-Nuclear receptor coactivator 4 (NCOA4) pathway represents a classical autophagic pathway involved in ferroptosis regulation. NCOA4 serves as a cargo receptor for the autophagic degradation of ferritin, a key protein complex responsible for iron storage. The degradation of ferritin via NCOA4-mediated autophagy releases free iron, which promotes lipid peroxidation and initiates ferroptotic cell death. Notably, environmental factors such as cigarette smoke can exacerbate ferroptosis by promoting unstable iron accumulation through NCOA4-mediated iron autophagy, highlighting the intricate interplay between environmental cues, cellular metabolism, and cell fate determination.

The significance of autophagy-dependent ferroptosis has been further underscored in various pathological conditions, including cancer. Studies have demonstrated that autophagy-dependent ferroptosis mediates tumor-associated macrophage polarization and influences tumor growth and progression, implicating ferroptosis as a potential target for cancer therapy.

The Complexities of Ferroptosis: Insights into Pathways and Pharmacological Applications

Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal player in various physiological and pathological processes. Recent research has shed light on the intricate pathways involved in the regulation of ferroptosis and its pharmacological implications in disease management.

Voltage-dependent anion channel (VDAC) stands out as a crucial transmembrane channel implicated in the transport of ions and metabolites, exerting a profound influence on ferroptosis regulation. The impact of erastin on VDAC function disrupts mitochondrial integrity, triggering the release of oxidizing agents and ultimately culminating in iron-mediated cell demise (4). However, ferroptosis is not solely governed by VDAC; rather, it is orchestrated by a network of interconnected pathways.

Beyond VDAC, several other pathways intricately regulate the occurrence of ferroptosis. The glutamine metabolic pathway, the p62-Keap1-NRF2 pathway, and squalene activity have all been implicated in modulating ferroptotic cell death (24, 57, 58). Nuclear factor erythroid 2-related factor 2 (NRF2), a pivotal player in the p62-Keap1-NRF2 pathway, emerges as a key regulator of antioxidant responses, safeguarding hepatocellular carcinoma (HCC) cells against ferroptosis. Mechanistically, the expression of p62 shields NRF2 from degradation, facilitating its nuclear translocation and subsequent antioxidant activity (57). Meanwhile, squalene, an antioxidant-like metabolite, exerts its protective effects against ferroptosis by modulating lipid profiles and downregulating squalene monooxygenase (SQLE) expression, thereby attenuating ferroptotic cell death in ALK+ anaplastic large cell lymphoma (ALCL) (58).

These pathways converge to modulate intracellular iron homeostasis and reactive oxygen species (ROS) levels, exerting a fine-tuned regulatory control over ferroptosis. Understanding the intricate interplay between these pathways is paramount for deciphering the mechanisms underlying ferroptosis and its implications in disease pathogenesis.

Moving beyond its physiological roles, ferroptosis has garnered considerable attention in the realm of pharmacology, offering promising avenues for disease intervention. Ferroptosis inducers and inhibitors have emerged as valuable tools for elucidating disease mechanisms and exploring therapeutic strategies.

Studies exploring ferroptosis inducers and inhibitors have unveiled their potential therapeutic applications across various diseases. By unraveling the mechanisms underlying ferroptosis, researchers have identified novel targets for therapeutic intervention. Ferroptosis inducers hold promise in combating diseases characterized by aberrant cell proliferation, such as cancer, while ferroptosis inhibitors offer potential avenues for mitigating tissue damage in conditions marked by oxidative stress.

Figure 1 Schematic illustration ferroptosis pathways. Regulatory mechanisms of ferroptosis are divided into three categories. The first pathway regulates iron metabolism, including Iron metabolic pathway, ATG5-ATG7-NCOA4 pathway, and P62-Keap1-NRF2 pathway. Second, it is regulated by the GSH/GPX4 pathway, including P53 pathway, System Xc-/GPX4 pathway, and Glutamine metabolic pathway. Third, it is associated with lipid metabolism, including Lipid metabolic pathway. In addition, Erastin acts on the mitochondria to induce ferroptosis. The FSP1-CoQ10-NAD(P)H and BH4-DHFR pathways exist as independent parallel systems, which cooperates with GPX4 and glutathione to inhibit phospholipid peroxidation and ferroptosis. MVA, mevalonate; GPX4, glutathione peroxidase 4; FSP1, ferroptosis suppressor protein 1; SAT1, spermine N1-acetyltransfersae 1; CDKN1A, cyclin-dependent kinase inhibitor 1A/P21; TF, transferrin; TFR1, transferrin receptor 1; DMT1, divalent metal ion transporter 1; ZIP8/14, zinc-iron regulatory protein family 8/14; HSPB1, Heat shock protein β-1; IREB2, iron response element-binding protein 2; HO-1, Heme oxygenase-1; FPN, Ferroportin; PUFAs, Polyunsaturated fatty acids; ACSL4, Acyl-CoA synthetase long-chain family member 4; LPCAT3, phospholipid choline acyltransferase 3; LOX, lipoxygenase; PE, phosphatidylethanolamine; NCOA4, Nuclear receptor coactivator 4; NRF2, nuclear factor erythroid 2-related factor 2; VDAC, Voltage- dependent anion channel; GCH1, cyclohydrolase-1; BH4, tetrahydrobiopterin; Gln, L-glutamine; Glu, L-glutamate.

The Role of Ferroptosis Modulators in Tumor Suppression and Neurodegenerative Disease Management

Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a promising avenue in both cancer therapy and the management of neurodegenerative diseases. This article delves into the intricate relationship between ferroptosis inducers and inhibitors and their potential applications in combating tumors and mitigating neurodegenerative conditions.

In the realm of tumor suppression, various compounds have shown efficacy in inducing ferroptosis across different cancer types. Artesunate, for instance, exhibits the ability to induce reactive oxygen species (ROS) production and activate ferroptosis in pancreatic cancer cell lines, thereby impeding pancreatic tumor progression (59). Similarly, molecules like piperamide, cyclophosphamide, and sulfasalazine have been found effective in promoting cell death in pancreatic cancer cells (60). Sorafenib, known for its ability to induce ferroptosis in liver cancer cells, has been employed in the treatment of advanced liver tumors (61). The sigma-1 receptor (S1R), highly expressed in hepatocytes, has been implicated in ferroptosis regulation, with its inhibition demonstrating potential in promoting cell death in hepatoma cells (62).

Furthermore, pathways such as the P62-Keap1-NRF2 axis play crucial roles in modulating ferroptosis in hepatocellular carcinoma cells, highlighting the complex interplay of molecular mechanisms in tumor cell fate determination (63). In gastric cancer, erastin serves as a potent inducer of ferroptosis, while cysteine dioxygenase type 1 (CDO1) emerges as a key regulator by competitively absorbing cysteine, thereby inhibiting glutathione (GSH) synthesis and promoting ferroptosis (63). In triple-negative breast cancer (TNBC), downregulation of the MUC1-C/System Xc- signaling pathway has been linked to ferroptosis induction, offering insights into potential therapeutic strategies targeting this aggressive cancer subtype (64). Similarly, in lung cancer, erastin-induced ferroptosis involves the activation of the P53 pathway, ultimately leading to ROS accumulation and cell death (65).

Melanoma studies have elucidated the role of miR-137 in negatively regulating ferroptosis by targeting the glutamine transporter SLC1A5, with its knockout promoting ferroptosis in melanoma cells (66). Additionally, in head and neck squamous cell carcinoma, dihydroartemisinin has demonstrated ferroptosis-inducing properties, underscoring the potential of ferroptosis as a therapeutic target across diverse cancer types (15). GPX4 inhibitors like RSL3 and ML-162 have also shown promise in inducing ferroptosis in head and neck cancer cells, suggesting a broader applicability of ferroptosis modulation in anti-tumor therapy (67).

Transitioning to neurodegenerative diseases, ferroptosis emerges as a significant player in the pathogenesis of conditions such as Parkinson’s, Huntington’s, and Alzheimer’s diseases. In Parkinson’s disease, characterized by dopaminergic neuron loss, ferroptosis modulation through agents like deferoxamine and ferrostatin-1 holds promise in alleviating oxidative stress and preserving neuronal integrity (68, 69). Similarly, in Huntington’s disease, where iron accumulation and glutathione dysregulation are prominent features, ferroptosis inhibition has shown protective effects on neurons (70, 71). The role of ferroptosis in Alzheimer’s disease pathogenesis is also evident, with elevated iron levels contributing to oxidative damage in affected brain regions (73, 74).

Implications Beyond Cancer and Neurodegenerative Diseases

Ferroptosis, initially recognized as a form of regulated cell death implicated in cancer and neurodegeneration, has garnered attention for its involvement in a spectrum of other diseases. This article delves into the multifaceted roles of ferroptosis inhibitors in mitigating pathological processes across various conditions, ranging from ischemic stroke to acute renal injury, and highlights emerging therapeutic avenues in inflammation modulation.

In the context of ischemic stroke, a notable decrease in glutathione (GSH) levels coupled with elevated lipid peroxidation and reduced glutathione peroxidase 4 (GPX4) activity in neurons underscores the involvement of ferroptosis in neuronal injury (75). Furthermore, studies in ischemic stroke mouse models have demonstrated the potential of ferroptosis inhibitors in improving prognostic outcomes for affected patients, shedding light on novel therapeutic strategies in stroke management (75).

The implications of ferroptosis extend beyond cerebral ischemia to encompass acute renal tubular necrosis and ischemia/reperfusion (I/R) injury. Notably, ferroptosis inhibitors have shown promise in alleviating renal tissue damage associated with these conditions (76). Research by Gao et al. highlights the therapeutic potential of targeting glutamine metabolism to suppress ferroptosis in I/R-induced tissue injury, providing insights into the mechanistic underpinnings of ferroptosis in renal pathology (24).

Moreover, the emergence of drug-tolerant persister cancer cells underscores the importance of GPX4 in tumor survival and recurrence. Hangauer et al. elucidated the dependency of persister cells on GPX4 and demonstrated the efficacy of GPX4 inhibition in inducing selective ferroptotic death of these cells in vitro, thus preventing tumor relapse in vivo (77). These findings underscore the therapeutic potential of targeting ferroptosis pathways in overcoming drug resistance and improving cancer treatment outcomes.

In recent years, the interplay between ferroptosis and inflammation has garnered significant attention. Ferroptosis-associated necrotizing inflammation has been observed in models of acute kidney injury (AKI) and in GPX4 deletion mice, highlighting the intricate relationship between ferroptosis and inflammatory responses (78). Activation of GPX4 has been implicated in mitigating inflammation by inhibiting the arachidonic acid (AA) and NF-κB pathways, thereby reducing intracellular ROS levels and suppressing ferroptosis-mediated inflammation (78). These insights pave the way for the development of novel anti-inflammatory and cytoprotective therapies targeting GPX4 activation.

Unveiling the Role of Diacyl-PUFA Phospholipids: Key Drivers of Ferroptosis

In a groundbreaking study published in Cell, scientists from Columbia University have uncovered a crucial link between a rare type of lipid and ferroptosis, a form of regulated cell death. Led by Dr. Brent Stockwell, whose team discovered ferroptosis in 2012, the research sheds new light on the mechanisms underlying this cell death pathway and holds promise for therapeutic interventions in various disease contexts, including neurodegenerative diseases and cancer.

The study, titled “Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis,” represents a collaborative effort between professors from Columbia’s departments of biological sciences, chemistry, and the Columbia University Irving Medical Center. Through meticulous investigation, the researchers aimed to elucidate the role of phospholipids with diacyl-PUFA tails (PL-PUFA2s) in ferroptosis, a process still poorly understood despite its significance in disease pathogenesis.

The researchers observed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following treatments with fatty acids or phospholipids, correlating with increased sensitivity to ferroptosis in cancer cells. Importantly, the depletion of PC-PUFA2s was evident in aging brains and Huntington’s disease-affected brain tissue, establishing a direct link between these lipids and ferroptosis in neurological disorders.

Further investigations revealed that PC-PUFA2s interact with the mitochondrial electron transport chain, leading to the generation of reactive oxygen species (ROS) crucial for initiating lipid peroxidation, a hallmark of ferroptosis. Mitochondria-targeted antioxidants demonstrated protective effects against PC-PUFA2-induced mitochondrial ROS, lipid peroxidation, and subsequent cell death, underscoring the critical role of these lipids in mitochondria homeostasis and ferroptosis regulation across diverse contexts.

The identification of diPUFA phospholipids as potent drivers of ferroptosis represents a significant milestone in understanding the molecular underpinnings of this cell death pathway. Moreover, these findings have implications for both diagnosis and therapy, with diPUFA lipids emerging as potential diagnostic markers and therapeutic targets for modulating ferroptosis in various diseases.

Dr. Stockwell emphasizes the transformative potential of harnessing diacyl-PUFA phospholipids in controlling cell death processes. By manipulating these lipids, researchers may gain insights into the occurrence of ferroptosis and develop targeted interventions to either induce or inhibit cell death, offering new avenues for disease treatment and management.

In conclusion, the discovery of diacyl-PUFA phospholipids as key regulators of ferroptosis represents a paradigm shift in our understanding of cell death mechanisms. Moving forward, harnessing the therapeutic potential of these lipids holds promise for advancing precision medicine and improving outcomes in diseases characterized by dysregulated cell death, marking a significant step towards unraveling the complexities of ferroptosis and its therapeutic implications.

Dietary Polyunsaturated Fatty Acids and Ferroptosis in Cancer: A Novel Therapeutic Approach

The intricate relationship between dietary polyunsaturated fatty acids (PUFAs) and ferroptosis in cancer cell lines opens up new avenues for cancer therapy. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal mechanism in cancer biology. The selective accumulation of PUFAs in cellular phospholipids (PLs) and their interaction with mitochondrial electron transport chain (ETC) complex I significantly influence ferroptosis induction.

Dietary PUFA and Its Role in Ferroptosis Induction

Dietary PUFAs, particularly when incorporated into cellular phospholipids as PC-PUFA2s, have been shown to induce ferroptosis in various cancer cell lines. This process is characterized by increased mitochondrial reactive oxygen species (ROS) production, essential for the execution of ferroptosis. The mechanistic insights into this phenomenon reveal that the selective increase in PC-PUFA2 accumulation within cells plays a critical role in ferroptosis induction. This is partly due to their interaction with mitochondrial ETC complex I, highlighting the significant impact of lipid metabolism on cancer cell viability.

The Molecular Pathways Influencing Ferroptosis

The role of ACSL4 in mediating PUFA incorporation into PLs and the subsequent induction of ferroptosis has been underscored in recent studies. Interferon-gamma (IFNγ), secreted by CD8+ T cells, in combination with arachidonic acid (AA), has been identified as a novel inducer of ferroptosis in cancer cells. This pathway involves the IFNγ-mediated upregulation of ACSL4, which enhances the incorporation of AA into PLs, thereby facilitating potent tumor cell ferroptosis. Furthermore, this process is shown to have an important role in anti-tumor immunity, suggesting the potential of dietary AA in combination with immune checkpoint inhibitors as a novel cancer treatment strategy.

The Interaction Between Ferroptosis and Lipid Metabolism

The susceptibility of cancer cells to ferroptosis is intricately linked to their altered lipid metabolism. The overexpression of ACSL4 in cancer cells enriches cellular membranes with long polyunsaturated ω-6 fatty acids, contributing to the production of lipid peroxides (LPO) and promoting sensitivity to ferroptosis. The regulation of ferroptosis by lipid metabolism is further highlighted by the role of hypoxia-inducible factors (HIFs) and the tumor suppressor p53 in modulating the cellular lipid landscape and ferroptosis susceptibility.

Implications for Cancer Therapy

The induction of ferroptosis through dietary PUFAs presents a promising therapeutic avenue in cancer treatment. By exploiting the vulnerabilities in cancer cell lipid metabolism and the regulatory mechanisms governing ferroptosis, it is possible to develop targeted therapies that selectively kill cancer cells while sparing normal cells. The ongoing research into the mechanisms of ferroptosis and its interaction with lipid metabolism in cancer underscores the potential of dietary interventions and pharmacological strategies in enhancing cancer therapy efficacy.

Further research in this field is essential to fully understand the therapeutic potential of inducing ferroptosis in cancer cells and to develop effective treatments that can leverage this mechanism to combat cancer.

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