Aims: Brown adipose tissue (BAT) relies heavily on mitochondrial activity and reactive oxygen species homeostasis to regulate thermogenesis and metabolic balance. However, the specific role of glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme and central regulator of ferroptosis, in BAT remains unclear. This study aims to investigate the necessity of GPX4 for the functional integrity and thermogenic capacity of BAT.

Methods: We generated a genetically engineered mouse model with a BAT-specific knockout of the Gpx4 gene. The physiological and metabolic impacts of GPX4 deficiency were evaluated across three different dietary contexts: cold exposure condition, high-fat diet, and vitamin E-deficient diet. Furthermore, RNA sequencing (RNA-seq) was conducted to analyze transcriptomic changes within the tissue.

Results: Phenotypic and metabolic analyses indicated that the absence of GPX4 does not impair the thermogenic function of BAT under any of the tested dietary conditions. Consistent with these physiological findings, RNA-seq revealed that GPX4 deficiency does not significantly alter the expression levels of genes associated with ferroptosis or thermogenic pathways.

Conclusion: Despite its crucial role in preventing ferroptosis in other tissues, GPX4 is not essential for maintaining the functional integrity and thermogenesis of BAT in mice under the specific physiological conditions tested.

Friedreich’s ataxia (FRDA) is a rare neurodegenerative condition driven by a severe deficiency of the mitochondrial protein frataxin (FXN). This depletion impairs mitochondrial iron-sulfur cluster biogenesis and disrupts intracellular iron homeostasis, ultimately promoting oxidative stress. Driven by localized iron overload and the continuous generation of reactive oxygen species, the resulting metabolic dysfunction renders vulnerable tissues highly susceptible to ferroptosis. This iron-dependent form of regulated cell death, executed through excessive lipid peroxidation, is now widely acknowledged as an important contributor to the neurodegeneration and hypertrophic cardiomyopathy that characterize FRDA. In the present review, we explore how FXN loss undermines cellular defenses against oxidative damage, placing a specific focus on the regulation of the lipid redox landscape. We detail the breakdown of glutathione (GSH)-dependent mechanisms, specifically highlighting the blunted Nrf2 antioxidant response and the subsequent reduced capacity of glutathione peroxidase 4. Alongside these deficits, we investigate the compensatory roles of GSH-independent rescue networks, namely ferroptosis suppressor protein 1 and mitochondrial dihydroorotate dehydrogenase. Looking toward clinical translation, we critically assess emerging pharmacological interventions designed to target these ferroptotic nodes. The potential of mitochondria-targeted iron chelators, lipoxygenase inhibitors, lipophilic radical-trapping antioxidants, and novel Nrf2 activators is evaluated to determine whether inhibiting ferroptosis can serve as a viable disease-modifying strategy. Moving forward, combinatorial “protect and restore” approaches will likely prove essential for maximizing therapeutic efficacy in FRDA.

Ferroptosis, a lipid peroxidation-driven form of regulated cell death, has emerged as a central mechanism in neurological disease. While most studies have focused on neuronal vulnerability, non-neuronal cells, including oligodendrocytes, astrocytes, microglia, brain endothelial cells, and central nervous system (CNS) infiltrating T cells, play equally critical roles in shaping disease progression. These cell types regulate iron homeostasis, lipid metabolism, antioxidant defenses, and inflammatory signaling, thereby establishing the microenvironmental conditions that determine ferroptotic susceptibility within the CNS. Accumulating evidence demonstrates lipid peroxidation and ferroptosis-related signaling in demyelinating disorders, ischemic injury, small vessel disease, Alzheimer’s disease, Parkinson’s disease, and spinal cord injury. However, the contribution of non-neuronal cells to ferroptotic stress and execution remains comparatively underexplored. In this review, we synthesize emerging data highlighting cell type-specific dependencies on glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1), nuclear factor erythroid 2-related factor 2 (NRF2), peroxiredoxin (PRDX), thioredoxin (TRX), iron-handling proteins, and lipid remodeling pathways, and discuss how these regulatory networks differ across CNS-resident and CNS infiltrating T cells. We propose that ferroptosis in neurological disease is not solely a neuron-autonomous event, but a tissue-level process orchestrated by non-neuronal cells with distinct metabolic and immunological programs. Understanding these cell type-specific vulnerabilities and regulatory mechanisms will be essential for the development of targeted therapeutic strategies aimed at modulating ferroptotic stress in neuroinflammatory and neurodegenerative disorders.

Iron is indispensable for cellular metabolism yet potentially cytotoxic, making its intracellular handling a fundamental determinant of cell fate decisions. The endo-lysosomal system has recently emerged as a central iron rheostat that integrates transferrin uptake, ferritinophagy, and lysosomal iron export to control iron bioavailability for mitochondria and other iron-dependent pathways. Growing studies further show that lysosomal iron is not merely permissive for ferroptosis but can directly initiate lipid damage through localized iron activation, lysosomal lipid peroxidation, and lysosomal membrane permeabilization. At the same time, emerging studies on organelle contact sites reveal that ferroptosis arises from the failure of a coordinated multi-organellar communication system, in which lysosomes, the endoplasmic reticulum, and mitochondria exchange iron, lipids, and redox signals in an effort to metabolically adapt to stress. This perspective is particularly relevant to drug-tolerant persisters and mesenchymal cancer cell states, which rely on rewired lysosomal iron trafficking to sustain plasticity while becoming highly susceptible to ferroptosis. In this minireview, we discuss emerging insights into the spatial organization of iron metabolism and propose a model in which ferroptosis sensitivity depends on the intracellular routing, chemical reactivity, and release dynamics of iron, highlighting lysosomal iron handling as a key therapeutic vulnerability in minimal residual disease.

Ferroptosis is an oxidative form of non-apoptotic cell death that is important for human biology. This process can be induced in cultured cells by at least four structurally and mechanistically distinct classes of ferroptosis inducing (FIN) small molecules. These four classes of FINs are distinguished based on molecular target and mechanism of action. The lethal mechanism of the prototypic oxime-containing class III FIN, FIN56, is unique and poorly understood. FIN56 is proposed to cause ferroptosis by depleting coenzyme Q10 and degrading glutathione peroxidase 4 (GPX4). Curiously, the FIN56 analogs caspase independent lethal 56 (CIL56) and tegavivint also trigger non-apoptotic cell death but not ferroptosis. Tegavivint is a drug candidate currently being tested in humans for the treatment of cancer. Here, we review our understanding of the FIN56 lethal mechanism with a view to guiding future investigations into a privileged chemical scaffold that possesses unusual lethal activity in cancer cells.