SLC7A11 is a cell transmembrane protein composing the light chain of system xc⁻, transporting extracellular cystine into cells for cysteine production and GSH biosynthesis. SLC7A11 is a critical gateway for redox homeostasis by maintaining the cellular levels of GSH that counter cellular oxidative stress and suppress ferroptosis. SLC7A11 is overexpressed in various human cancers and regulates tumor development, proliferation, metastasis, microenvironment, and treatment resistance. Upregulation of SLC7A11 in cancers is needed to adapt to high oxidative stress microenvironments and maintain cellular redox homeostasis. High basal ROS levels and SLC7A11 dependences in cancer cells render them vulnerable to further oxidative stress. Therefore, cyst(e)ine depletion may be an effective new strategy for cancer treatment. However, the effectiveness of the SLC7A11 inhibitors or cyst(e)inase has been established in many preclinical studies but has not reached the stage of clinical trials for cancer patients. A better understanding of cysteine and SLC7A11 functions regulating and interacting with redox-active proteins and their substrates could be a promising strategy for cancer treatment. Therefore, this review intends to understand the role of cysteine in antioxidant and redox signaling, the regulators of cysteine bioavailability in cancer, the role of SLC7A11 linking cysteine redox signaling in cancer metabolism and targeting SLC7A11 for novel cancer therapeutics.

Iron is essential for life. Many enzymes require iron for appropriate function. However, dysregulation of intracellular iron homeostasis produces excessive reactive oxygen species (ROS) via the Fenton reaction and causes devastating effects on cells, leading to ferroptosis, an iron-dependent cell death. In order to protect against harmful effects, the intracellular system regulates cellular iron levels through iron regulatory mechanisms, including hepcidin–ferroportin, divalent metal transporter 1 (DMT1)–transferrin, and ferritin–nuclear receptor coactivator 4 (NCOA4). During iron deficiency, DMT1–transferrin and ferritin–NCOA4 systems increase intracellular iron levels via endosomes and ferritinophagy, respectively. In contrast, repleting extracellular iron promotes cellular iron absorption through the hepcidin–ferroportin axis. These processes are regulated by the iron-regulatory protein (IRP)/iron-responsive element (IRE) system and nuclear factor erythroid 2-related factor 2 (Nrf2). Meanwhile, excessive ROS also promotes neuroinflammation by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB forms inflammasomes, inhibits silent information regulator 2-related enzyme 1 (SIRT1), and induces pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β). Furthermore, 4-hydroxy-2,3-trans-nonenal (4-HNE), the end-product of ferroptosis, promotes the inflammatory response by producing amyloid-beta (Aβ) fibrils and neurofibrillary tangles in Alzheimer’s disease, and alpha-synuclein aggregation in Parkinson’s disease. This interplay shows that intracellular iron homeostasis is vital to maintain inflammatory homeostasis. Here, we review the role of iron homeostasis in inflammation based on recent findings.

Ferroptosis, a recently identified form of regulated cell death characterized by the iron-dependent accumulation of lethal lipid peroxidation, has gained increasing attention in cancer therapy. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone oxidoreductase that reduces ubiquinone to ubiquinol, has emerged as a critical player in the regulation of ferroptosis. FSP1 operates independently of the canonical system xc^–/glutathione peroxidase 4 pathway, making it a promising target for inducing ferroptosis in cancer cells and overcoming ferroptosis resistance. This review provides a comprehensive overview of FSP1 and ferroptosis, emphasizing the importance of FSP1 modulation and its potential as a therapeutic target in cancer treatment. We also discuss recent progress in developing FSP1 inhibitors and their implications for cancer therapy. Despite the challenges associated with targeting FSP1, advances in this field may provide a strong foundation for developing innovative and effective treatments for cancer and other diseases.

Ferroptosis, a regulated form of iron-dependent lipid peroxidation-induced cell death, has emerged as a compelling therapeutic strategy to overcome treatment resistance in head and neck cancer (HNC). Glutathione peroxidase 4 (GPX4), a selenoenzyme responsible for detoxifying phospholipid hydroperoxides, plays a central role in blocking ferroptosis and is frequently upregulated in therapy-resistant HNC subtypes. In this review, we examine the multifaceted regulation of GPX4 expression and function, including transcriptional, post-transcriptional, epigenetic, and proteostatic mechanisms. We explore how GPX4 suppression through pharmacologic inhibitors (e.g., RSL3, withaferin A, statins), metabolic stress, or combined therapies (e.g., radiotherapy, EGFR inhibitors, immunotherapy) induces ferroptosis and resensitizes resistant tumors. We also summarize emerging biomarkers, including GPX4, ACSL4, SLC7A11, and NCOA4, that predict ferroptosis sensitivity and may guide patient selection for ferroptosis-targeted therapies. Single-cell and spatial transcriptomics reveal significant intratumoral heterogeneity in ferroptosis susceptibility, underscoring the need for precision approaches. Despite promising preclinical data, challenges such as drug delivery, toxicity, and resistance mechanisms remain. Nevertheless, the ferroptosis-GPX4 axis represents a unique vulnerability in HNC that can be therapeutically exploited. Integrating ferroptosis modulation into personalized oncology may transform outcomes for patients with refractory disease.