Aging is a natural biological process that is characterized by the progressive decline in physiological functions and an increased vulnerability to age-related diseases. The aging process is driven by different cell and molecular mechanisms. It has recently been shown that aging is associated with heightened vulnerability to ferroptosis (an intracellular iron-dependent form of programmed cell death). This susceptibility arises from various factors including oxidative stress, impaired antioxidant defences, and dysregulated iron homeostasis. The progressive decline in cellular antioxidant capacity and the accumulation of damaged components contribute to the increased susceptibility of aging cells to ferroptosis. Dysregulation of key regulators involved in ferroptosis, such as glutathione peroxidase 4 (GPX4), iron regulatory proteins, and lipid metabolism enzymes, further exacerbates this vulnerability. The decline in cellular defence mechanisms against ferroptosis during aging contributes to the accumulation of damaged cells and tissues, ultimately resulting in the manifestation of age-related diseases. Understanding the intricate relevance between aging and ferroptosis holds significant potential for developing strategies to counteract the detrimental effects of aging and age-related diseases. This will subsequently act to mitigate the negative consequences of aging and improving overall health in the elderly population. This review aims to clarify the relationship between aging and ferroptosis, and explores the underlying mechanisms and implications for age-related disorders, including neurodegenerative, cardiovascular, and neoplastic diseases. We also discuss the accumulating evidence suggesting that the imbalance of redox homeostasis and perturbations in iron metabolism contribute to the age-associated vulnerability to ferroptosis.

Chronic arsenic exposure enhances the probability of lung cancer with the underlying mechanisms remain unknown. Glutamine-driven synthetic metabolism, including nucleotide synthesis, amino acid production, TCA cycle replenishment, glutathione synthesis, and lipid biosynthesis, is crucial for both cancer initiation and progression. This study demonstrated that chronic exposure to 0.1 μM arsenite for as long as 36 weeks induced malignant transformation in human bronchial epithelial cells (BEAS-2B). Metabolomics were used to systematically disclose metabolic characteristics in arsenic-transformed malignant (As-TM) cells. Significantly changed metabolites were enriched in alanine, aspartate and glutamate metabolism, arginine biosynthesis, glutamine and glutamate metabolism, glutathione metabolism, butanoate metabolism, TCA cycle, and arginine and proline metabolism. It is worth noting that glutamate located at the intersection of the enriched metabolism pathways. Glutamine deprivation attenuated the oncogenic phenotypes, including capacity of wound healing and proliferation, in As-TM cells. And the expression levels of mRNA and proteins associated with glutamine metabolism-related transporters and enzymes, including SLC7A11, GCLM, and GCLC, were significantly increased, with SLC7A11 exhibiting the most substantial increase. Moreover, arsenite transformation progressively elevated SLC7A11 mRNA and protein levels over time. The SLC7A11 inhibitor sulfasalazine remarkably attenuated arsenite-induced oncogenic phenotypes. Collectively, our data suggest that chronic arsenite exposure enhances glutamine metabolism through upregulation of SLC7A11, thereby promoting cell proliferation and malignant transformation. These results provide new insights for preventive and therapeutic strategies for lung cancer linked to arsenic exposure.

Lysosomes maintain an acidic pH of 4.5-5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H+ ATPase, proton efflux is mediated by a fast H+ leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate, two H+ equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis, as well as facilitated α-synuclein aggregation in neurons. Correction of abnormal lysosomal acidity restored lysosome homeostasis and prevented ferroptosis. These studies have revealed an unconventional H+ transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson's disease (PD) pathology.

Nonalcoholic steatohepatitis (NASH) has been identified as a significant risk factor contributing to the rising incidence of hepatocellular carcinoma (HCC). With the evolving epidemiological characteristics of NASH, the incidence of NASH-related HCC has increased substantially. Recent advances in the study of regulated cell death (RCD) mechanisms have uncovered their roles in the pathogenesis of NAFLD/NASH and associated HCC, offering novel insights and directions for targeted therapeutic strategies. Although numerous studies have highlighted the critical role of RCD mechanisms in NAFLD/NASH and related HCC, significant challenges remain in developing effective targeted therapies and translating them into clinical applications. This review aims to summarize the current progress in understanding the role of RCD in NAFLD/NASH and associated HCC, explore potential therapeutic strategies and clinical applications, and provide new perspectives and therapeutic targets for treating NAFLD/NASH. Ultimately, the goal is to control disease progression at the NAFLD/NASH stage and prevent its progression to HCC.

There is a continuous increase in the incidence of thyroid cancer. A deeper understanding of the molecular mechanisms of thyroid cancer could significantly improve thyroid cancer management. Newly discovered type of programmed cell death, ferroptosis, has been demonstrated to play a crucial role in many cancers. Mounting evidence shows that there is a close association between ferroptosis and thyroid cancer, which offer a promising therapeutic strategy for thyroid cancer. Ferroptosis is expected to emerge as a novel therapeutic target. Regrettably, the exact role of ferroptosis in thyroid cancer is not yet completely understood. Further, there is currently no summary of ferroptosis in thyroid cancer progression and treatment. Hence, in this review, we aim to revisit the pathological process of thyroid cancer and reveal the role of ferroptosis in thyroid cancer. In addition, we provide evidence that ferroptosis inducers could suppress the growth of thyroid cancer cells. Lastly, we discuss the potential application of ferroptosis inducers in thyroid cancer treatment, as well as possible impediments and corresponding strategies. The relationship between ferroptosis and thyroid cancer will be better understood through this review, which may offer a novel insight into thyroid cancer therapy.

Ferroptosis is a type of iron‑dependent cell death characterized by excessive lipid peroxidation and may serve as a potential therapeutic target in cancer treatment. While the mechanisms governing ferroptosis continue to be explored and elucidated, an increasing body of research highlights the significant impact of epigenetic modifications on the sensitivity of cancer cells to ferroptosis. Epigenetic processes, such as DNA methylation, histone modifications and non‑coding RNAs, have been identified as key regulators that modulate the expression of ferroptosis‑related genes. These alterations can either enhance or inhibit the sensitivity of gastrointestinal cancer (GIC) cells to ferroptosis, thereby affecting the fate of GICs. Drugs that target epigenetic markers for advanced‑stage cancer have shown promising results in enhancing ferroptosis and inhibiting tumor growth. This review explores the intricate relationship between epigenetic regulation and ferroptosis in GICs. Additionally, the potential of leveraging epigenetic modifications to trigger ferroptosis in GICs is investigated. This review highlights the importance of further research to elucidate the specific mechanisms underlying epigenetic control of ferroptosis and to advance the development of novel therapeutic approaches.

Persistent inflammation leading to neuronal sensitization in pain pathways, are key features of chronic inflammatory pain. Alike macrophages in the periphery, glial cells exacerbate hypersensitivity by releasing proalgesic mediators in the central nervous system. Expressed by peripheral and central immune cells, the cystine-glutamate antiporter system xc- plays a significant role in inflammatory responses, but its involvement in chronic inflammatory pain remains underexplored. We herein investigated the contribution of this exchanger in nociceptive hypersensitivity triggered by a peripheral inflammatory insult.

Complete Freund's adjuvant (CFA) was injected into the left hind paw of wild-type C57Bl/6 female mice, of xCT-deficient mice (specific subunit of system xc-) and of mice receiving the system xc- inhibitor sulfasalazine. Paw edema was measured over three weeks and pain-associated behaviors were evaluated. Additionally, pro-inflammatory cytokine levels were assessed in blood samples.

CFA injection led to a persistent increase in paw edema and hypersensitivity to mechanical and thermal stimuli, which were less pronounced in xCT-deficient mice. This reduced sensitivity was accompanied by lower systemic pro-inflammatory cytokine levels in xCT-deficient mice. Accordingly, pharmacological inhibition of system xc- with sulfasalazine, either before or after pain induction, efficiently reduced the algesic and inflammatory responses to CFA in wild-type mice.

Our findings reveal a critical role for system xc- in the pathophysiology of inflammatory pain. xCT deficiency reduces pain behaviors and peripheral inflammation, positioning system xc- as a promising therapeutic target for alleviating chronic inflammatory pain.

N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by KIT or PDGFRA mutations. Programmed cell death (PCD), including apoptosis, autophagy, and ferroptosis, plays a crucial role in GIST pathogenesis, progression, and treatment response. Non-coding RNAs (ncRNAs) have emerged as key regulators of PCD pathways, influencing GIST proliferation, metastasis, and drug resistance, particularly in response to tyrosine kinase inhibitors (TKIs) such as imatinib. Apoptosis suppression is strongly associated with poor prognosis, while autophagy contributes to tumor dormancy and TKI resistance. Ferroptosis, a novel iron-dependent cell death pathway, represents a promising therapeutic target. Recent evidence suggests that ncRNAs modulate these PCD pathways through interactions with key molecular regulators such as miR-494, miR-30a, and lncRNAs, which affect signaling networks including PI3K/AKT, MAPK, and mTOR. Furthermore, ncRNAs have mediated secondary resistance to imatinib by promoting autophagic flux and altering ferroptosis sensitivity. Understanding the molecular interplay between ncRNAs and PCD in GIST provides novel insights into disease mechanisms and offers potential therapeutic strategies to overcome drug resistance. Targeting ncRNA-mediated regulation of apoptosis, autophagy, and ferroptosis may enhance treatment efficacy and improve patient outcomes. Future research should focus on elucidating the mechanistic roles of ncRNAs in PCD pathways to develop innovative diagnostic and therapeutic approaches for GIST.

Iron dysregulation has emerged as a pivotal factor in neurodegenerative pathologies, especially through its capacity to promote ferroptosis, a unique form of regulated cell death driven by iron-catalyzed lipid peroxidation. This review synthesizes current evidence on the molecular underpinnings of ferroptosis, focusing on how disruptions in iron homeostasis interact with key antioxidant defenses, such as the system Xc--glutathione-GPX4 axis, to tip neurons toward lethal oxidative damage. Building on these mechanistic foundations, we explore how ferroptosis intersects with hallmark pathologies in Alzheimer's disease (AD) and Parkinson's disease (PD) and examine how iron accumulation in vulnerable brain regions may fuel disease-specific protein aggregation and neurodegeneration. We further surveyed the distinct components of ferroptosis, highlighting the role of lipid peroxidation enzymes, mitochondrial dysfunction, and recently discovered parallel pathways that either exacerbate or mitigate neuronal death. Finally, we discuss how these insights open new avenues for neuroprotective strategies, including iron chelation and lipid peroxidation inhibitors. By highlighting open questions, this review seeks to clarify the current state of knowledge and proposes directions to harness ferroptosis modulation for disease intervention.

Tumor tissues exhibit elevated oxidative stress, with the cystine-glutamate transporter xCT solute carrier family 7 member 11 (xCT/SLC7A11) protecting cancer cells from oxidative damage by facilitating cystine uptake for glutathione synthesis. Disulfidptosis, a newly identified form of programmed cell death (PCD), occurs in cells with high xCT/SLC7A11 expression under glucose-deprived conditions. Distinct from other PCD pathways, disulfidptosis is characterized by aberrant disulfide bond formation and cellular dysfunction, ultimately resulting in cancer cell death. This novel mechanism offers remarkable therapeutic potential by targeting the inherent oxidative stress vulnerabilities of rapidly growing cancer cells. Advances in nanotechnology enable the development of nanomaterials capable of inducing reactive oxygen species (ROS) generation, disrupting disulfide bonds. In addition, they are capable to deliver therapeutic agents directly to tumors, thereby improving therapeutic precision and minimizing off-target effects. Moreover, combining disulfidptosis with ROS-induced immunogenic cell death can remodel the tumor microenvironment and enhance anti-tumor immunity. This review explores the mechanisms underlying disulfidptosis, its therapeutic potential in cancer treatment, and the synergistic role of nanotechnology in amplifying its effects. Selective induction of disulfidptosis using nanomaterials represents a promising strategy for achieving more effective, selective, and less toxic cancer therapies.

Ferroptosis is a form of regulated cell death driven by the accumulation of iron-dependent lipid peroxides, and ferroptosis-mediated cancer therapy has gained considerable attention. Despite emerging evidence that ferroptosis induction effectively suppresses hepatocellular carcinoma (HCC) progression and enhances chemosensitivity, the development of resistance to ferroptosis-targeting therapies remains a critical challenge. Natural active compounds have great potential in cancer treatment.

The impact of 6-ME on the cell viability of HCC cells was assessed using the Cell Counting Kit-8 (CCK-8) assay and colony formation assay. Furthermore, cellular morphology of HCC cells was visualized under inverted fluorescence microscopy. Intracellular reactive oxygen species (ROS) and lipid peroxidation levels were quantified using fluorescence probes and determined by flow cytometry analysis. The expression of ferroptosis-related proteins and genes was determined via Western blot and quantitative real-time PCR analyses.

Here, we demonstrate that 6-Methoxydihydrosanguinarine (6-ME), an alkaloid from Macleaya cordata, exerts anti-tumor functions in HCC cells via ferroptosis. Stimulation with 6-ME induces intracellular ROS production, cell growth inhibition, and cell death in HCC cells, and these effects can be weakened by the ROS scavenger GSH or NAC and ferroptosis inhibitors deferoxamine mesylate (DFO) or ferrostatin-1 (Fer-1). Mechanistically, 6-ME downregulates the expression of the key ferroptosis defense enzyme GPX4 at the transcriptional level, leading to excessive lipid peroxidation and ferroptosis in HCC cells. Importantly, low concentrations of 6-ME also enhanced the ferroptosis sensitivity induced by RSL3 and IKE in HCC cells.

These findings reveal that the natural product 6-ME exerts anti-tumor functions in HCC cells via ferroptosis and underscore the potential of 6-ME administered alone or in combination with canonical ferroptosis inducers for the treatment of HCC patients.

Sensorineural hearing loss (SNHL), the most commonly-occurring form of hearing loss, is caused mainly by injury to or the loss of hair cells and spiral ganglion neurons in the cochlea. Numerous environmental and physiological factors have been shown to cause acquired SNHL, such as ototoxic drugs, noise exposure, aging, infections, and diseases. Several programmed cell death (PCD) pathways have been reported to be involved in SNHL, especially some novel PCD pathways that have only recently been reported, such as ferroptosis, necroptosis, and pyroptosis. Here we summarize these PCD pathways and their roles and mechanisms in SNHL, aiming to provide new insights and potential therapeutic strategies for SNHL by targeting these PCD pathways.

Ferroptosis is a necrotic, non-apoptotic cell death modality triggered by unrestrained iron-dependent lipid peroxidation. By unveiling the regulatory mechanisms of ferroptosis and its relevance to various diseases, research over the past decade has positioned ferroptosis as a promising therapeutic target. The rapid growth of this research field presents challenges, associated with potentially inadequate experimental approaches that may lead to misinterpretations in the assessment of ferroptosis. Typical examples include assessing whether an observed phenotype is indeed linked to ferroptosis, and selecting appropriate animal models and small-molecule modulators of ferroptotic cell death. This Expert Recommendation outlines state-of-the-art methods and tools to reliably study ferroptosis and increase the reproducibility and robustness of experimental results. We present highly validated compounds and animal models, and discuss their advantages and limitations. Furthermore, we provide an overview of the regulatory mechanisms and the best-studied players in ferroptosis regulation, such as GPX4, FSP1, SLC7A11 and ACSL4, discussing frequent pitfalls in experimental design and relevant guidance. These recommendations are intended for researchers at all levels, including those entering the expanding and exciting field of ferroptosis research.

Lenvatinib, endorse as a first-line targeted therapy, has demonstrated efficacy in extending the survival span of individuals afflicted with advanced Hepatocellular carcinoma (HCC). However, its therapeutic effect wears off with time, which is ascribed to the cancer cell's tendency to evade and tamper with its usual modes of action, severely limiting its clinical use. This study devises an innovative therapeutic modality involving the synergistic co-delivery of FePt nanoparticles (NPs) and Lenvatinib via poly lactic-co-glycolic acid (PLGA) NPs encase in HCC cell membranes (Len/FePt@CMP NPs). The investigation explores the mechanism through which Lenvatinib induces ferroptosis in HCC, notably by dampening the glutathione peroxidase 4 (GPX4) through the inhibition of fibroblast growth factor receptor 4. FePt NPs are engineered to enhance the efficacy of ferroptosis and apoptosis for HCC treatment. Concurrently, the incorporation of the cancer cell membrane facilitates the targeted accumulation of NPs at the tumor site, leveraging mechanisms of immune evasion and homologous targeting. This enhances ferroptosis/apoptosis treatment efficacy, triggeres by Len/FePt@CMP NPs, is convincingly demonstrated both in vitro and in vivo. The proposed approach has the potential to redefine HCC therapeutic paradigms by overcoming mono-therapeutic limitations in current clinical treatments, showcasing the improved efficacy of a comprehensive strategy.

Sorafenib is a commonly used first-line kinase-targeted drug for advanced hepatocellular carcinoma (HCC) patients suffering from limited efficacy. Emerging evidence indicates that sorafenib exerts anti-cancer activity through the induction of ferroptosis in HCC cells, but the underlying mechanism is still unclear.

The whole transcriptome sequencing and bioinformatics analysis were used to screen for target genes. The expression and subcellular localization of regulatory factor X1 (RFX1) were determined through immunohistochemistry, immunofluorescence, PCR and western blot analyses. The impact of RFX1 on HCC cell growth was assessed using CCK8, colony formation assays, cell death assays, and animal experiments. Glutathione measurement, iron assay and lipid peroxidation detection assays were performed to investigate ferroptosis of HCC cells. The regulatory mechanism of RFX1 in HCC was investigated by sgRFX1, co-IP, ChIP and luciferase experiments. Immunohistochemical and survival analyses were performed to examine the prognostic significance of RFX1 in HCC.

In this study, we found that RFX1 promote ferroptosis in HCC cells. Further, we showed that sorafenib induces cell death through RFX1-mediated ferroptosis in HCC cells. The enhancing effect of RFX1 on HCC cell ferroptosis is largely dependent on inhibition of cystine/glutamate antiporter (system Xc-) activity through the BECN-SLC7A11 axis, where RFX1 directly binds to the promoter region of BECN1 and upregulates BECN1 expression. In addition, a STAT3-RFX1-BECN1 signalling loop was found to promote RFX1 expression in HCC cells.

Our study reveals a novel mechanism underlying sorafenib-induced HCC cell death.

Subacute ruminal acidosis can cause liver injury in ruminants. Ferroptosis, an iron-dependent cell death, is involved in many liver diseases. This study aimed to investigate ferroptosis in SARA-induced liver injury and explore the changes in hepatic iron metabolism. Twelve ruminally cannulated, lactating Hu sheep (parity: 2 or 3; BW: 50.6 ± 4.0 kg; 18.8 ± 3.6 DIM; MY: 0.52 ± 0.08 kg/d; mean ± SD) were divided into 2 groups (n = 6/group) and fed a low-grain diet (LG; grain/forage ratio = 3:7, 24.89% starch and 40.66% NDF) or a high-grain diet (HG; grain/forage ratio = 7:3, 38.64% starch and 24.41% NDF) for 8 wk. Rumen pH was measured weekly 10 min before feeding and 1, 2, 3, 4, 5, 6, and 8 h after feeding. On d 57, all sheep were slaughtered after collecting hepatic vein blood, and liver tissue was collected. The HG diet significantly decreased rumen pH compared with the LG diet; the rumen pH on d 56 in the HG group was <5.6 at 1, 2, 3, and 4 h after feeding. Plasma concentrations of LPS, malondialdehyde (MDA), IL-1β, and IL-6 at 4 h after feeding increased, whereas glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased. Moreover, lipid reactive oxygen species, ferrous ion, and MDA were elevated, whereas GSH was decreased in the liver of the HG group. For ferroptosis-related proteins, feeding a high-grain diet led to increased acyl-CoA synthetase long chain family member 4 (ACSL4) and arachidonate 15-lipoxygenase (ALOX15) and decreased GPX4 and solute carrier family 7 member 11 (SLC7A11). For ferritinophagy-related proteins, feeding a high-grain diet decreased ferritin heavy chain 1 (FTH1) and increased nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain 3 II (MAP1LC3-II). Regarding iron metabolism, increased protein expression of nuclear mothers against decapentaplegic homolog1/5/8 (SMAD1/5/8) and hepcidin, decreased protein expression of ferroportin, and iron deposits were observed in the liver of the HG group. Furthermore, feeding high-grain diets also increased inflammatory signaling-related proteins IL-6 and phospho-signal transducer and activator of transcription 3 (p-STAT3). Taken together, this study suggests that SARA induced liver injury and ferroptosis. Enhanced ferritinophagy, disordered iron metabolism, and elevated inflammatory response may mediate ferroptosis in the livers of sheep fed a high-grain diet.

We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate, and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain, and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K, and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system, and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and proferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide, and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression, and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.

Boron neutron capture therapy (BNCT) perform as a treatment option for locally advanced or recurrent unresectable head and neck cancers since June 2020 in Japan. The effect of BNCT on parotid carcinoma, which presents a variety of histologic types, remains unclear. The object of this study was to investigate the antitumor efficacy of BNCT against parotid gland carcinoma by focusing on LAT1, which is involved in the uptake of L-BPA, the boron compound used in BNCT.

We performed a retrospective review of 42 high-grade parotid gland carcinoma cases. We immunostained specimens using an anti-LAT1 monoclonal antibody to assess the LAT1 expression rate. We divided the patients into two groups: LAT1 expression rate below 10% (negative group) and 10% or higher (positive group), and performed a survival rate analysis.

The study included 42 patients categorized by histological three type into mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), and adenoid cystic carcinoma (AdCC). The LAT1 expression rate in the 42 cases was 37.5%, and the rates for each histological type were: AdCC 15.0%; MEC 17.5%; and SDC 60.0%. The 5-year disease-free survival (DFS) rates were 46.8% in the positive group and 81.8% in the negative group (p = 0.17).

The LAT1 expression rate was 37.5% in cases of high-grade parotid gland carcinoma, and SDC exhibited particularly high expression. From the perspective of LAT1 expression, our results indicated that L-BPA-based BNCT is likely to achieve therapeutic efficacy against parotid gland carcinoma.

Ruminal dysbiosis-induced liver injury is prevalent in dairy cows, yet its underlying mechanisms remain incompletely understood. Ferroptosis, a newly identified form of programmed cell death distinct from apoptosis and necrosis, has been implicated in various liver diseases by emerging studies. In the present study, lipopolysaccharide (LPS) and γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) were employed to establish in vitro and in vivo models of liver injury using bovine hepatocytes and mice, respectively. It was observed that noncytotoxic iE-DAP alone did not influence lipid peroxidation or GPX4, but exacerbated LPS-induced ferroptosis and hepatocyte injury. Notably, co-treatment with LPS and iE-DAP (LPS/iE-DAP)-induced hepatocyte injury was mitigated by intervention with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, the activated IL-6/STAT3 signaling pathway was found to mediate LPS/iE-DAP-induced ferroptosis. Suppression of IL-6/STAT3, either through IL6 and STAT3 knockdown or pharmacological intervention, reduced Fe2+ accumulation and alleviated ferroptotic cell death. Further investigations identified that IL-6/STAT3 signaling enhanced ferritinophagy and impaired iron export. Either disrupting ferritinophagy by knocking down NCOA4 or restoring iron export via HAMP knockdown relieved intracellular iron overload and inhibited ferroptosis. Specifically, LPS/iE-DAP treatment increased the interaction between hepcidin and ferroportin, promoting ferroportin ubiquitination and degradation, thereby blocking iron efflux. Furthermore, we provided several evidence to prove that quercetin pretreatment alleviated LPS/iE-DAP-induced ferroptosis and liver injury by decreasing hepatic iron accumulation via targeting the IL-6/STAT3 signaling in vitro and in vivo, effects reversed by the addition of recombinant bovine IL-6. Based on these findings, we concluded that LPS/iE-DAP-induced liver injury by triggering ferroptosis through regulating IL-6/STAT3/ferritinophagy-dependent iron release and IL-6/STAT3/hepcidin/ferroportin-dependent iron export, while quercetin could alleviate this liver injury by inhibiting ferroptosis via IL-6/STAT3 signaling pathway. This study provides novel insights into the mechanisms whereby ruminal dysbiosis induces liver injury and presents a prospective solution for ruminal dysbiosis-induced liver injury.

Flavonoids are a class of important polyphenolic compounds, renowned for their antioxidant properties. However, recent studies have uncovered an additional function of these natural flavonoids: their ability to inhibit ferroptosis. Ferroptosis is a key mechanism driving cell death in central nervous system (CNS) diseases, including both acute injuries and chronic neurodegenerative disorders, characterized by iron overload-induced lipid peroxidation and dysfunction of the antioxidant defense system. This review discusses the therapeutic potential of natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in CNS diseases, focusing on their molecular mechanisms, summarizing findings from preclinical animal models, and providing insights for clinical translation. We specifically highlight natural flavonoids such as Baicalin, Baicalein, Chrysin, Vitexin, Galangin, Quercetin, Isoquercetin, Eriodictyol, Proanthocyanidin, (-)-epigallocatechin-3-gallate, Dihydromyricetin, Soybean Isoflavones, Calycosin, Icariside II, and Safflower Yellow, which have shown promising results in animal models of acute CNS injuries, including ischemic stroke, cerebral ischemia-reperfusion injury, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury. Among these, Baicalin and its precursor Baicalein stand out due to extensive research and favorable outcomes in acute injury models. Mechanistically, these flavonoids not only regulate the Nrf2/ARE pathway and activate GPX4/GSH-related antioxidant pathways but also modulate iron metabolism proteins, thereby alleviating iron overload and inhibiting ferroptosis. While flavonoids show promise as ferroptosis inhibitors for CNS diseases, especially in acute injury settings, further studies are needed to evaluate their efficacy, safety, pharmacokinetics, and blood-brain barrier penetration for clinical application.

In recent 10 years, ferroptosis has become a hot research direction in the scientific research community as a new way of cell death. Iron toxicity accumulation and lipotoxicity are unique features. Several studies have found that ferroptosis is involved in the regulation of the hepatic microenvironment and various hepatic metabolisms, thereby mediating the progression of related liver diseases. For example, NRF2 and FSP1, as important regulatory proteins of ferroptosis, are involved in the development of liver tumors and liver failure. In this manuscript, we present the mechanisms involved in ferroptosis, the concern of ferroptosis with the liver microenvironment and the progression of ferroptosis in various liver diseases. In addition, we summarize recent clinical advances in targeted ferroptosis therapy for related diseases. We expect that this manuscript can provide a new perspective for clinical treatment of related diseases.

Although a fraction of functional peptides concealed within long non-coding RNAs (lncRNAs) is identified, it remains unclear whether lncRNA-encoded peptides are involved in the malignancy of cervical cancer (CC). Here, a 92-amino acid peptide is discovered, which is named TUBORF, encoded by lncRNA TUBA3FP and highly expressed in CC tissues. TUBORF inhibits ferroptosis to promote the malignant proliferation of CC cells. Mechanistically, human papillomavirus (HPV) oncogenes E6 and E7 upregulate TUBORF through CREB-binding protein (CBP)/E1A-binding protein p300 (p300)-mediated histone H3 lysine 27 acetylation (H3K27ac) of lncTUBA3FP enhancer. Furthermore, E6 and E7 elevate and recruit acetyltransferase establishment of sister chromatid cohesion N-acetyltransferase 1 (ESCO1) to bind to and acetylate TUBORF, which facilitates the degradation of immunity-related GTPase Q (IRGQ) via a ubiquitin-proteasome pathway, resulting in the inhibition of ferroptosis and promotion of the malignant proliferation of CC cells. Importantly, silencing ESCO1 or TURORF amplifies anticancer effects by paclitaxel both in CC cells and in vivo. These novel findings reveal oncopeptide TUBORF and its acetyltransferase ESCO1 as important regulators of ferroptosis and tumorigenesis during cervical cancer pathogenesis and establish the scientific basis for targeting these molecules for treating CC.

Changyanning tablets (CYN) are a marketed traditional Chinese medicine composed of Diijincao (Euphorbia humifusa Willd.), Jinmaoercao (Hedyotis chrysotricha (Palib.) Merr.), Zhangshugen (root of Cinnamomum camphora (L.) J.Presl), Xiangru (Elsholtzia ciliate (Thunb.) Hyl.), and Fengxiangshuye (leaf of Liquidambar formosana Hance). They possess the functions of clearing heat, removing dampness, and regulating qi. CYN is used for the treatment of diarrhea and dysentery caused by damp heat in the large intestine, with symptoms such as diarrhea, or stools with pus and blood, tenesmus, abdominal pain and distension, acute and chronic gastroenteritis, diarrhea, bacterial diarrhea, and indigestion in children.

This study aims to explore the intervention effects of CYN on Crohn's disease (CD) and its potential mechanisms.

The therapeutic effect and potential mechanism of CYN on CD were investigated based on the 2,4,6-Trinitrobenzenesulfonic acid solution (TNBS)-induced rat model. In vivo and in vitro experiments confirmed that CYN can alleviate CD by inhibiting GPX4-mediated ferroptosis. siRNA was used to knock down GPX4 for reverse validation. Finally, active components of CYN inhibiting ferroptosis were identified using UPLC-MS and the RSL3-induced HCoEpiC ferroptosis cell model.

CYN significantly improved ferroptosis-related indicators (GSH, MDA, GPX4, and SLC7A11) in the colons of TNBS-induced CD rats. Screening with three ferroptosis inducers (RSL3, FINO2, and erastin) revealed that CYN was most effective against RSL3 (a ferroptosis inducer targeting GPX4)-induced apoptosis. Subsequently, the resistance effect of CYN on RSL3-induced ferroptosis was confirmed in vitro. Further in vivo experiments showed that CYN alleviated local CD-like intestinal injury induced by RSL3 enema. siRNA knockdown of GPX4 in HCoEpiC cells further validated GPX4 as major target of CYN in inhibiting ferroptosis. Finally, UPLC-MS and in vitro experiments identified rutin, rosmarinic acid, and kaempferol-3-O-sophoroside as key active components of CYN for inhibiting ferroptosis.

CYN alleviates CD by inhibiting GPX4-mediated ferroptosis, highlighting its clinical potential for treating CD and enhancing the understanding of the pathogenic and therapeutic mechanisms associated with CD.

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

Fluoride exposure in drinking water has been widely related to impairment of cognitive function. Even though this ion has been described as neurotoxic for more than two decades, the molecular mechanisms of fluoride neurotoxicity are not fully understood, however, increasing evidence suggests that glial cells are the site of early injury in fluoride neurotoxicity. Nevertheless, a convergence point of many studies is the effect on glutamatergic neurotransmission and the generation of reactive oxygen species. In this context, we evaluated here the expression and regulation of the cystine/glutamate exchanger upon fluoride exposure since this transporter is in the interface between excitotoxicity and the antioxidant response. We demonstrate here the functional expression of the cystine /glutamate exchanger in both the U373 human glioblastoma cells and chick cerebellar Bergmann glia cells. Using a [3H]-L-Glutamate uptake assay, we demonstrate that fluoride increases the activity of the exchanger in a time and dose-dependent manner. This augmentation is mitigated by the antioxidant Trolox. To gain insight into fluoride neurotoxicity mechanisms, we evaluated its effect on human antigen R, a RNA binding protein, that binds to the 3'-UTR region of exchanger mRNA increasing its half time life. An increase in human antigen R protein was recorded after a 6 h fluoride exposure, suggesting that this ion regulates the exchanger through this RNA-binding protein. Furthermore, we show that fluoride exposure increases both the exchanger and human antigen R mRNAs half-life. These results provide insights into fluoride neurotoxicity mechanisms and support the notion of a central role of glial cells in neuronal glutamatergic transmission disruption that leads to neuronal cell death.

Disulfidptosis, a novel form of metabolism-related regulated cell death, is a promising intervention for cancer therapeutic intervention. Although aberrant expression of long-chain noncoding RNAs (lncRNAs) expression has been associated with pancreatic carcinoma (PC) development, the biological properties and prognostic potential of disulfidptosis-related lncRNAs (DRLs) remain unclear.

We obtained RNA-seq data, clinical data, and genomic mutations of PC from the TCGA database, and then determined DRLs. We developed a risk score model and analyzed the role of risk score in the predictive ability, immune cell infiltration, immunotherapy response, and drug sensitivity.

We finally established a prognostic model including three DRLs (AP005233.2, FAM83A-AS1, and TRAF3IP2-AS1). According to Kaplan-Meier curve analysis, the survival time of patients in the low-risk group was significantly longer than that in the high-risk group. Based on enrichment analysis, significant associations between metabolic processes and differentially expressed genes were assessed in two risk groups. In addition, we observed significant differences in the tumor immune microenvironment landscape. Tumor Immune Dysfunction and Rejection (TIDE) analysis showed no statistically significant likelihood of immune evasion in both risk groups. Patients exhibiting both high risk and high tumor mutation burden (TMB) had the poorest survival times, while those falling into the low risk and low TMB categories showed the best prognosis. Moreover, the risk group identified by the 3-DRLs profile showed significant drug sensitivity.

Our proposed 3-DRLs-based feature could serve as a promising tool for predicting the prognosis, immune landscape, and treatment response of PC patients, thus facilitating optimal clinical decision-making.

Sepsis-associated acute lung injury (SALI) is a common complication of sepsis, consisting of a dysfunctional host response to infection-mediated heterogenous complexes. SALI is reported in up to 50 % of patients with sepsis and causes poor outcomes. Despite high incidence, there is a lack of understanding in its pathogenesis and optimal treatment. A better understanding of the molecular mechanisms underlying SALI may help produce better therapeutics. The effects of altered cell-death mechanisms, such as non-apoptotic regulated cell death (RCD) (i.e., ferroptosis), on the development of SALI are beginning to be discovered, while targeting ferroptosis as a meaningful target in SALI is increasingly being recognized. Here, we outline how a susceptible lung alveoli may develop SALI. Then we discuss the general mechanisms underlying ferroptosis, and how it contributes to SALI. We then outline the chemical structures of the emerging agents or compounds that can protect against SALI by inhibiting ferroptosis, summarizing their potential pharmacological effects. Finally, we highlight key limitations and possible strategies to overcome them. This review suggests that a detailed mechanistic and biological understanding of ferroptosis can foster the development of pharmacological antagonists in the treatment of SALI.

Aortic dissection (AD) is a life-threatening vascular condition marked by the separation or tearing of the aortic media. Ferroptosis, a form of iron-dependent programmed cell death, occurs alongside lipid peroxidation and the accumulation of reactive oxygen species (ROS). The relationship between ferroptosis and AD lies in its damaging effect on vascular cells. In AD, ferroptosis worsens the damage to vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), thereby weakening the vascular wall's structural integrity and accelerating the onset and progression of the condition. However, the molecular mechanisms through which ferroptosis regulates the onset and progression of AD remain poorly understood. This article explores the relationship between ferroptosis and AD.

One of the underlying mechanisms of epilepsy (EP), a brain disease characterized by recurrent seizures, is considered to be cell death. Disulfidptosis, a proposed novel cell death mechanism, is thought to play a part in the pathogenesis of epilepsy, but the exact role is unclear. The gene expression omnibus series (GSE) 33000 and GSE63808 datasets were used to search for differentially expressed disulfidptosis-related molecules (DE-DRMs). A correlation between the DE-DRMs was discovered. Individuals with epilepsy were then used to investigate molecular clusters based on the expression of DE-DRMs. Following that, the best machine learning model which is validated by GSE143272 dataset and predictor molecules were identified. The correlation between predictive molecules and clinical traits was determined. Based on the in vitro and in vivo seizures models, experimental analyses were applied to verify the DE-DRMs expressions and the correlation between them. Nine molecules were identified as DE-DRMs: glycogen synthase 1 (GYS1), solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), 3-oxoacyl-ACP synthase, mitochondrial (OXSM), leucine rich pentatricopeptide repeat containing (LRPPRC), NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), NUBP iron‑sulfur cluster assembly factor, mitochondrial (NUBPL), and NCK associated protein 1 (NCKAP1). NDUFS1 interacted with NDUFA11, NUBPL, and LRPPRC, while SLC3A2 interacted with SLC7A11. The optimal machine learning model was revealed to be the random forest (RF) model. G protein guanine nucleotide-binding protein alpha subunit q (GNAQ) was linked to sodium valproate resistance. The experimental analyses suggested an upregulated SLC7A11 expression, an increased number of formed SLC3A2 and SLC7A11 complexes, and a decreased number of formed NDUFS1 and NDUFA11 complexes. This study provides previously undocumented evidence of the relationship between disulfidptosis and EP. In addition to suggesting that SLC7A11 may be a specific DRM for EP, this research demonstrates the alterations in two disulfidptosis-related protein complexes: SLC7A11-SLC3A2 and NDUFS1-NDUFA11.

Cytotoxic effects of cigarette smoke are thought to be causes of cigarette smoking-related diseases such as respiratory infection, chronic obstructive pulmonary disease, and atherosclerosis. Unsaturated carbonyl compounds are major cytotoxic factors in the gas phase of cigarette smoke. Cell death induced by unsaturated carbonyl compounds in cigarette smoke is PKC-dependent ferroptosis. Although the cell sensitivity to unsaturated carbonyl compounds varies by cell types, the molecular mechanisms underlying this sensitivity remain unclear. In this study, we have examined the factors involved in determining sensitivity to unsaturated carbonyl compounds. We found that two mouse macrophage cell lines exhibited different sensitivities; J774.1 macrophages were sensitive to unsaturated carbonyl compounds, whereas RAW264.7 macrophages were resistant. Glutathione synthesis inhibitor increased the sensitivity of RAW264.7 macrophages to unsaturated carbonyl compounds. Quantitative RT-PCR revealed that the expression level of the cystine transporter SLC7A11 was higher in RAW264.7 macrophages than in J774.1 macrophages. Inhibition of SLC7A11 activity increased sensitivity to unsaturated carbonyl compounds, while overexpression of SLC7A11 enhances resistance to these compounds. The current results suggest that the SLC7A11 level is a key factor in determining the macrophage sensitivity to unsaturated carbonyl compounds.

Ferroptosis is a regulated cell death mechanism distinct from apoptosis, autophagy, and necroptosis, marked by iron accumulation and lipid peroxidation. Since its identification in 2012, it has developed into a potential therapeutic target, especially concerning GI disorders like PC, HCC, GC, and CRC. This interest arises from the distinctive role of ferroptosis in the progression of diseases, presenting a new avenue for treatment where existing therapies fall short. Recent studies emphasize the promise of focusing on ferroptosis to fight GI cancers, showcasing its unique pathophysiological mechanisms compared to other types of cell death. By comprehending how ferroptosis aids in the onset and advancement of GI diseases, scientists aim to discover novel drug targets and treatment approaches. Investigating ferroptosis in gastrointestinal disorders reveals exciting possibilities for novel therapies, potentially revolutionizing cancer treatment and providing renewed hope for individuals affected by these tumors.

Prostate cancer is the second most common type of cancer in male worldwide. Stromal-epithelial interaction is thought to have a major impact on cancer development and progression. Previous studies have shown that interaction via soluble factors lead to a reduction in the expression of xCT and AL122023.1 in the prostate carcinoma cell line LNCaP after seven days of co-culture with primary stromal p21 cells. In this study, we validated the repression of xCT and AL122023.1 at RNA level using quantitative real-time PCR and at protein level by Western Blotting. Furthermore, xCT is known to be a putative target for miRNAs miR-26a, miR-30d and miR-30e, which in turn potentially interact with AL122023.1. The lncRNA-miRNA-interaction was verified by luciferase reporter assays. However, miR-26a/-30d/-30e did not inhibit xCT expression at protein level. Nevertheless, indirect inhibitory effect of AL122023.1 on the xCT expression could be shown. Moreover, immunostaining revealed precise xCT expression in neuroendocrine cells, ranging from fetal, healthy juvenile, and adult prostate tissue to benign prostatic hyperplasia and finally advanced prostate cancer. This study explores the relevance and function of xCT and AL122023.1 in the prostate and exposes xCT as a potential marker or therapeutic target in high-risk prostate cancer.

Astrocytes produce and export glutathione (GSH), an important thiol antioxidant essential for protecting neural cells from oxidative stress and maintaining optimal brain health. While it has been established that oxidative stress increases GSH production in astrocytes, with Nrf2 acting as a critical transcription factor regulating key components of the GSH synthetic pathway, the role of Nrf2 in controlling constitutive GSH synthetic and release mechanisms remains incompletely investigated. Our data show that naïve primary mouse astrocytes cultured from the cerebral cortices of Nrf2 knockout (Nrf2-/-) pups have significantly less intracellular and extracellular GSH levels when compared to astrocytes cultured from Nrf2 wild-type (Nrf2+/+) pups. Key components of the GSH synthetic pathway, including xCT (the substrate-specific light chain of the substrate-importing transporter, system xc-), glutamate-cysteine ligase [catalytic (GCLc) and modifying (GCLm) subunits], were affected. To wit: qRT-PCR analysis demonstrates that naïve Nrf2-/- astrocytes have significantly lower basal mRNA levels of xCT and both GCL subunits compared to naïve Nrf2+/+ astrocytes. No change in mRNA levels of glutathione synthetase (GS) or the GSH exporting transporter, Mrp1, was found. Western blot analysis reveals reduced protein levels of both subunits of GCL, while (seleno)cystine uptake into Nrf2-/- astrocytes was reduced compared to Nrf2+/+ astrocytes, confirming decreased system xc- activity. These findings suggest that Nrf2 regulates the basal production of GSH in astrocytes through constitutive transcriptional regulation of GCL and xCT.

Ulcerative colitis (UC), a form of inflammatory irritable bowel disease, is characterized by a recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis.

The protective effect of PD on colitis was examined in cultured caco-2 cells and DSS-induced colitis mouse model. Bulk RNA sequencing and differential gene expression analysis were used to investigate the protective mechanism of PD on DSS-induced colitis. Ferroptosis was determined by MDA levels, SOD levels, mitochondrial iron accumulation and ROS production. Ferroptosis-related proteins Slc7a11, Nrf2 and Gpx4 levels were measured by western blot, immunohistochemical and immunofluorescence staining.

PD mitigated the DSS-induced increases in pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), alleviated colon length shortening, reduced morphological damage to the intestinal mucosa, and preserved tight junction proteins (TJ) occludin and Zonula occludens-1 (ZO-1) in both caco-2 cells and murine models of colitis. Mechanistically, PD reversed the reduction of Nrf2, Slc7a11 and Gpx4, the degree of nuclear translocation of Nrf2 induced by DSS in vitro and in vivo significantly. Moreover, the protective effect of PD is attenuated by erastin and resembled that of Fer-1 in caco-2 cells model.

Our study suggested that PD protects against DSS-induced ulcerative colitis via Nrf2/Slc7a11/Gpx4-dependent inhibition of ferroptosis signalling activation. Further investigation into the precise mechanisms underlying this phenomenon is warranted. The findings presented herein indicated that PD may serve as a potential therapeutic agent for patients with UC.