Search Results (8)

Background: Diabetic cardiomyopathy (DCM), a common cardiovascular complication associated with diabetes mellitus, has the potential to progress to heart failure. Apocynum venetum L. leaves extract (AVLE) possesses known cardioprotective activity, but its effect on DCM remains unclear. This study explored the protective effects of AVLE against myocardial injury in type 2 diabetes and the underlying mechanisms. Methods: DCM was established in vivo using db/db mice and in vitro using high-glucose, high-fat (HGHF)-stimulated H9c2 cardiomyocytes. We evaluated metabolic profiles, cardiac function, histopathology, oxidative stress, inflammation, and ferroptosis. Results: In vivo, following 12 weeks of AVLE treatment, cardiac function and structural integrity were significantly improved, serum cardiac injury markers and dyslipidemia were reduced, and pathological myocardial remodeling was attenuated in db/db mice; in vitro, AVLE enhanced cell viability and attenuated cellular damage under HGHF conditions. Mechanistically, AVLE alleviated oxidative stress and inflammation, restored mitochondrial function, and inhibited ferroptosis by regulating key pathway proteins; it upregulated GPX4 and SLC7A11, while downregulating TfR1 and ACSL4. Conclusions: AVLE exerts cardioprotective effects against diabetic cardiomyopathy by reducing oxidative stress and inflammation, mitigating lipid peroxidation and mitochondrial damage, ultimately inhibiting ferroptosis through regulation of the Xc⁻/GSH/GPX4 axis. Full article

Pancreatic ductal adenocarcinoma (PDAC) shows substantial heterogeneity in cysteine dependence and ferroptosis sensitivity. We identify two PDAC subtypes distinguished by EMT status: mesenchymal-like cells are highly cysteine-dependent and rapidly undergo ferroptosis upon cystine deprivation or system xc⁻ inhibition, whereas epithelial-type cells are ferroptosis-resistant. Selenium supplementation protects cells from erastin-induced ferroptosis, and this protection persists even when intracellular glutathione (GSH) is depleted, supporting an additional GPX4-independent protective mechanism. Sepp1 knockdown does not alter sensitivity, indicating that selenium’s protective effect is independent of Sepp1. Instead, epithelial-type cells rely on both cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) to maintain ferroptosis resistance. Chemical inhibition of thioredoxin reductases abolishes selenium-mediated protection and sensitizes epithelial cells to ferroptosis inducers, while dual genetic suppression of TrxR1 and TrxR2 similarly restores ferroptosis sensitivity. These findings uncover a selenium–thioredoxin redox axis that functions independently of GPX4 and contributes ferroptosis resistance in epithelial-type PDAC cells. Co-targeting cysteine metabolism and thioredoxin reductases may therefore represent a rational strategy to overcome ferroptosis resistance in some PDAC subtypes. Full article

Ferroptosis is an iron-dependent form of regulated cell death (RCD) characterized by intracellular iron homeostasis disruption and lipid peroxide accumulation. It is involved in many pathological processes, including malignant tumors, cardiovascular diseases, inflammatory diseases, and mitochondrial disorders. Cysteine desulfurase (NFS1), a key enzyme in mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, participates in regulating cellular ferroptosis by maintaining Fe-S cluster homeostasis and modulating the ACO1/IRP1 axis, the Xc⁻–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis, and the p53/STAT signaling pathway. When the function of NFS1 is abnormal, the intracellular free iron level is elevated, followed by reactive oxygen species (ROS) accumulation and lipid peroxidation. NFS1 expression exhibits significant variation across different tissues. Upregulation of NFS1 in tumors can enhance tumor cell resistance to ferroptosis; thus, it can promote tumor growth, drug resistance, and metastatic ability. Conversely, downregulation of NFS1 in cardiomyocytes and neurons exacerbates ferroptosis and causes functional impairment. Here, we systematically review recent advances in the molecular mechanisms of NFS1-mediated ferroptosis and its role in various disease models, intending to clarify key components in the upstream regulatory network of ferroptosis and explore the application value of NFS1 as a potential therapeutic target. The review shows that NFS1 plays an important role in cellular fate regulation, which has significant clinical application potential in the treatment of cancer and interventions for neurological and cardiovascular diseases. Therefore, it can provide a new theoretical basis and research direction for subsequent mechanism research and targeted therapeutic strategy development. Full article

Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a critical pathogenic mechanism and a highly promising therapeutic target in sensorineural hearing loss (SNHL). The irreversible loss of auditory hair cells, the hallmark of SNHL, creates an urgent need for novel therapeutic strategies. This review provides a translational perspective on ferroptosis, connecting its core molecular machinery to tangible opportunities for otoprotection. We systematically analyze three key targetable nodes: the iron metabolic pathways that fuel the process; the lipid peroxidation machinery that executes membrane damage; and the collapse of the System Xc⁻–GSH–GPX4 antioxidant axis. By framing the disease mechanism through these actionable targets, we highlight a clear rationale for developing new hearing preservation therapies. We conclude by surveying the most promising pharmacological approaches, including iron chelators, radical-trapping antioxidants, and bioactive natural products, offering a strategic roadmap for future drug discovery in audiology. Full article

Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a key player in the pathogenesis of gastrointestinal (GI) diseases. Unlike apoptosis or necrosis, ferroptosis is characterized by distinctive metabolic and molecular pathways, including dysregulated iron metabolism, oxidative stress, and impaired antioxidant defenses. This review explores the complex role of ferroptosis in conditions such as inflammatory bowel disease (IBD), non-alcoholic steatohepatitis (NASH), and gastrointestinal cancers. Special attention is given to the molecular mechanisms underlying ferroptosis, including the Xc⁻/GSH/GPX4 axis, ferritinophagy, ACSL4/LPCAT3-mediated lipid remodeling, and the influence of the gut microbiota. Therapeutic strategies targeting ferroptosis—including pharmacological inhibitors, iron chelators, and microbiota-based interventions—are evaluated for their translational potential, underscoring ferroptosis as a promising target for precision therapies in gastroenterology and highlighting the need for further clinical studies to validate its diagnostic and therapeutic implications. Full article

Background/Objectives: Colorectal cancer (CRC) is characterized by a high rate of both incidence and mortality, and its treatment outcomes are often affected by recurrence and drug resistance. Ferroptosis, an iron-dependent programmed cell death mechanism triggered by lipid peroxidation, has recently gained attention as a potential therapeutic target. Graphene oxide (GO), known for its oxygen-containing functional groups, biocompatibility, and potential for functionalization, holds promise in cancer treatment. However, its role in ferroptosis induction in CRC remains underexplored. The objective of this study was to investigate the effects of High Carbonyl Graphene Oxide (HC-GO) on ferroptosis in CRC and elucidate the underlying mechanisms. Methods: In vitro assays were conducted to evaluate the impact of HC-GO on CRC cell proliferation, mitochondrial function, iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) production. The ferroptosis inhibitor Fer-1 was used to confirm the role of ferroptosis in HC-GO’s anti-tumor effects. In vivo, the anti-tumor activity of HC-GO was assessed in a CRC xenograft model, with organ toxicity evaluated. Results: HC-GO significantly inhibited CRC cell proliferation, induced mitochondrial damage, and enhanced iron accumulation, lipid peroxidation, and ROS production. It also downregulated the ferroptosis-inhibiting proteins GPX4 and SLC7A11, which were reversed by Fer-1, confirming the involvement of ferroptosis in HC-GO’s anti-cancer effects. In vivo, HC-GO significantly suppressed tumor growth without noticeable toxicity to vital organs. Conclusions: HC-GO triggered ferroptosis in CRC cells by suppressing the System Xc−/GSH/GPX4 pathway, providing a novel therapeutic strategy for CRC treatment. These findings suggest HC-GO as a promising nanomedicine for clinical application, warranting further investigation to explore its potential in CRC therapy. Full article

Cells employ a well-preserved physiological stress response mechanism, termed the heat shock response, to activate a certain type of molecular chaperone called heat shock proteins (HSPs). HSPs are activated by transcriptional activators of heat shock genes known as heat shock factors (HSFs). These molecular chaperones are categorized as the HSP70 superfamily, which includes HSPA (HSP70) and HSPH (HSP110) families; the DNAJ (HSP40) family; the HSPB family (small heat shock proteins (sHSPs)); chaperonins and chaperonin-like proteins; and other heat-inducible protein families. HSPs play a critical role in sustaining proteostasis and protecting cells against stressful stimuli. HSPs participate in folding newly synthesized proteins, holding folded proteins in their native conformation, preventing protein misfolding and accumulation, and degrading denatured proteins. Ferroptosis is a recently identified type of oxidative iron-dependent cell demise. It was coined recently in 2012 by Stockwell Lab members, who described a special kind of cell death induced by erastin or RSL3. Ferroptosis is characterized by alterations in oxidative status resulting from iron accumulation, increased oxidative stress, and lipid peroxidation, which are mediated by enzymatic and non-enzymatic pathways. The process of ferroptotic cell death is regulated at multiple, and it is involved in several pathophysiological conditions. Much research has emerged in recent years demonstrating the involvement of HSPs and their regulator heat shock factor 1 (HSF1) in ferroptosis regulation. Understanding the machinery controlling HSF1 and HSPs in ferroptosis can be employed in developing therapeutic interventions for ferroptosis occurrence in a number of pathological conditions. Therefore, this review comprehensively summarized the basic characteristics of ferroptosis and the regulatory functions of HSF1 and HSPs in ferroptosis. Full article

Parkinson disease (PD) is the second-most common neurodegenerative disease. The characteristic pathology of progressive dopaminergic neuronal loss in people with PD is associated with iron accumulation and is suggested to be driven in part by the novel cell death pathway, ferroptosis. A unique modality of cell death, ferroptosis is mediated by iron-dependent phospholipid peroxidation. The mechanisms of ferroptosis inhibitors enhance antioxidative capacity to counter the oxidative stress from lipid peroxidation, such as through the system x_c⁻/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis and the coenzyme Q10 (CoQ10)/FSP1 pathway. Another means to reduce ferroptosis is with iron chelators. To date, there is no disease-modifying therapy to cure or slow PD progression, and a recent topic of research seeks to intervene with the development of PD via regulation of ferroptosis. In this review, we provide a discussion of different cell death pathways, the molecular mechanisms of ferroptosis, the role of ferroptosis in blood–brain barrier damage, updates on PD studies in ferroptosis, and the latest progress of pharmacological agents targeting ferroptosis for the intervention of PD in clinical trials. Full article