Glaucoma is an ocular disease and a leading cause of irreversible blindness, driven by progressive retinal ganglion cell (RGC) loss. While elevated intraocular pressure (IOP) is a major risk factor, RGC degeneration often persists despite effective IOP-lowering therapy. This persistence suggests the involvement of pressure-independent pathogenic mechanisms. Growing evidence implicates ferroptosis – an iron-dependent, oxidative form of regulated cell death –as a critical contributor to RGC loss in glaucoma. It is characterized by iron accumulation, lipid peroxidation, antioxidant (glutathione) depletion, and mitochondrial dysfunction in degenerating RGCs. Dysregulated iron metabolism and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy promote iron overload. Simultaneously, impairment of the glutathione-GPX4 axis compromises lipid peroxide detoxification, which converges with oxidative stress and glutamate excitotoxicity, to drive a self-amplifying cycle of RGC ferroptotic death. Preclinical studies show that ferroptosis inhibitors, iron chelators, NRF2 activators, MAPK inhibitors, hydrogen sulfide donors, and natural antioxidants protect RGCs and preserve retinal function. These findings highlight ferroptosis as a promising therapeutic target. Targeting ferroptotic pathways, either alone or in combination with IOP-lowering strategies, may improve long-term visual outcomes. Future research should focus on optimizing therapeutic combinations, assessing safety, and facilitating clinical translation.

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and cellular antioxidant defenses, is a critical driver of various pathological states. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) serves as the master regulator of redox homeostasis, counteracting oxidative stress by orchestrating the expression of genes involved in glutathione biosynthesis, iron metabolism, and lipid peroxidation detoxification. Recently, the specific induction of lipid peroxidation has been identified as the hallmark of ferroptosis, a form of regulated cell death that represents a promising vulnerability for cancer therapy. However, cancer cells frequently hijack the NRF2 pathway to suppress ferroptosis, thereby promoting tumor survival, metastasis, and therapy resistance. Here, we comprehensively summarize the multi-layered regulatory mechanisms of NRF2, spanning transcriptional, post-transcriptional, and post-translational modifications, within the specific context of the ferroptosis-cancer axis. We further discuss how aberrant NRF2 signaling confers ferroptosis resistance in malignancy and highlight emerging therapeutic strategies that target the NRF2 pathway to reignite ferroptotic cell death in tumors. A deeper understanding of these regulatory networks is essential for the development of precision ferroptosis-based cancer therapies.

Sulfur, like oxygen, belongs to group 16 of the periodic table and exhibits remarkable versatility in both electron donation and acceptance, as well as in its wide range of oxidation states. These properties enable sulfur to participate in diverse redox reactions, while also serving as a critical component of enzyme active sites and redox sensors. Moreover, sulfur is the only element capable of forming stable linear homonuclear chains, a property known as catenation, which gives rise to a rich array of naturally occurring allotropes with complex chemical architectures. Recent advances in analytical technologies have uncovered the in vivo existence of supersulfides, molecules containing catenated sulfur atoms, whose physiological functions and pathological relevance are now beginning to be elucidated. In this review, we highlight the unique chemical features and biological functions of supersulfur species, with a particular focus on their roles in cancer. Furthermore, we discuss the therapeutic implications of supersulfur-driven “reductive stress,” a distinct imbalance in redox homeostasis that may be exploited for cancer treatment.

Ferroptosis, a non-apoptotic regulated cell death culminating in iron-dependent lipid peroxidation, has rapidly emerged as an additional mechanism of neuronal death after stroke. Yet, despite converging molecular features, such as the collapse of antioxidant systems and oxidation of lipids, the upstream biochemical landscapes that trigger ferroptosis differ across ischemic and hemorrhagic injury. In this review, we examine ferroptosis as an emergent property of redox network failure, where the transcriptional, metabolic, and oxidative circuits that normally sustain neuronal resilience are interrupted. Cells continuously operate within a spectrum of oxidative eustress and distress, balancing reactive species that serve as physiological signals and limiting their ability to inflict irreversible damage. Within this continuum, eustress supports adaptive redox signaling, metabolic coupling, and repair, whereas distress reflects exhaustion of reducing power and a shift toward self-propagative oxidation. Drawing on evidence from our lab and others, we explore how distinct stress inputs drive neurons and glia along this continuum toward ferroptotic collapse following each stroke subtype; much of this work originated within reductionist in vitro ferroptotic models and has since been extended to in vivo models. Understanding ferroptosis after stroke not only as a graded failure of redox homeostasis but also an evolutionarily adapted mechanism to couple neuronal injury to the reparative immune response is essential. Effective neuroprotective strategies will therefore depend on identifying and targeting the context-specific triggers and temporal windows that define each stroke subtype.

Aims: Non-enzymatic autoxidation of polyunsaturated fatty acids (PUFAs), generating numerous toxic by-products implicated in neurodegeneration, aging, and other pathologies, is a key process in ferroptosis. Lipid peroxidation (LPO) can be inhibited by deuterated polyunsaturated fatty acids (D-PUFA), as the rate-limiting step of abstraction of bis-allylic hydrogen atoms is slowed down by replacing the bis-allylic hydrogens with deuteriums. Here, we aimed to assess the protective effect of monounsaturated fatty acids (MUFA), which do not undergo LPO, as compared to that of various D-PUFAs, in a liposomal model of LPO.

Methods: To detect LPO induced by ferrous ions in liposomes, we used the LPO fluorescent probe C11-Bodipy (581/591), in addition to measuring conjugated diene and malondialdehyde accumulation.

Results: By applying the C11-Bodipy (581/591) probe, we found that both 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and 1-stearoyl-2-(11,11-d₂-linoleoyl)-phosphatidylcholine (D2-Lin-PC) protect non-deuterated 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine (H-Lin-PC) liposomes from LPO. Similarly, both POPC and 1-stearoyl-2-(11,11,14,14-D4-linolenyl)-phosphatidylcholine (D4-Lnn-PC) protect 1-stearoyl-2-linolenyl-phosphatidylcholine (H-Lnn-PC), and so does 1-stearoyl-2-(6,6,9,9,12,12,15,15,18,18-d10-docosahexaenoyl)-sn-glycero-3-phosphatidylcholine (D10-DHA-PC). The conjugated diene and malondialdehyde probes also showed similar protective effects of POPC and D-PUFA on LPO in H-Lnn-PC.

Conclusion: Obviously, the presence of non-oxidizable lipids, such as POPC, similar to the deuterated lipids D2-Lin-PC, D4-Lnn-PC, and D10-DHA-PC, leads to a sharp decrease in the length of lateral propagation of chain reactions in lipid membranes, but they do not participate in LPO themselves.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Recent evidence indicates that ferroptosis is a critical player associated with cell death and inflammatory processes in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in chronic inflammation. In addition, during aging, the expression and activity of various proteins and cellular processes associated with the ferroptotic pathway, such as lipid peroxidation, have been shown to be altered. In this review, we introduce the concept of xenoferroptosis, a process in which ferroptotic signalling is amplified through the combined action of distinct challenges: one involving sub-threshold ferroptosis-related mechanisms, and another involving sub-toxic levels of exogenous or endogenous stressors. Exogenous challenges, such as air pollutants, pesticides, and micro- or nanoplastics, can disrupt redox balance through increased reactive oxygen species production, and impaired antioxidant defences. Endogenous triggers could include misfolded, aggregated proteins, such as amyloid-beta, hyperphosphorylated tau, and alpha-synuclein, which sensitize cells by promoting redox imbalance and mitochondrial dysfunction. While each individual stressor, either endogenous/exogenous or ferroptotic-associated process, may be sublethal, their convergence would initiate a synergistic cascade that accelerates cell death. We propose that xenoferroptosis represents a distinct pathogenic axis at the intersection of molecular pathology and environmental exposure, offering new perspectives for therapeutic interventions that target its dual-trigger mechanisms.

Ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, has been extensively studied since its conceptualization in 2012 and has been suggested as a therapeutic target in many cancers and degenerative diseases. However, three fundamental questions remain unanswered about ferroptosis. First, the mechanisms by which cells execute death during ferroptosis remain elusive: The key role of lipid peroxides in triggering ferroptosis is established, but how this results in the death of a cell remains unclear. Second, the physiological role of ferroptosis throughout the human life cycle is unclear; currently, there is evidence for ferroptosis in early development, immunity, aging, and tumor suppression, but not in many other aspects of physiology. Third, and finally, the intersection between ferroptosis and other RCD modalities, such as apoptosis, necroptosis, pyroptosis, and autophagic cell death, is necessary for understanding how ferroptosis integrates into networks controlling cellular fate. Addressing these gaps in knowledge is essential for building a comprehensive understanding of this mode of cell death, as well as translating ferroptosis knowledge into effective therapeutics.