SLC7A11/GPX4 pathway

Overview

The SLC7A11/GPX4 pathway is the two-step supply line that protects membranes from lipid peroxidation, and its interruption is the canonical route to ferroptosis. SLC7A11 (solute carrier family 7 member 11) imports cystine, which is reduced to cysteine — the rate-limiting substrate for glutathione synthesis — and GPX4 then uses that glutathione to reduce lipid hydroperoxides to unreactive alcohols. GPX4 is a selenoprotein, with selenocysteine in its active site, which makes it uniquely efficient at reducing peroxidized phospholipids within membranes and also makes the whole defense dependent on selenium supply. Disrupting either step depletes antioxidant capacity and permits iron-dependent death with excessive reactive oxygen species and uncontrolled peroxidation: cystine starvation or transporter inhibition acts upstream, while compounds such as RSL3 inactivate GPX4 directly, which is why cells can be killed by either route.

Control operates at both ends. SLC7A11 transcription responds to NRF2, TP53 and ATF4 — p53 repressing it, the others inducing it — with signaling regulators such as the NAD⁺-dependent deacetylase SIRT1 acting indirectly rather than as transcription factors themselves. GPX4 is controlled post-translationally, including ubiquitin-mediated degradation coordinated by E3 ligases such as TRIM55, and a parallel defense through FSP1-regenerated coenzyme Q10 explains why GPX4 loss is not uniformly lethal.

Clinically the axis is a target in both directions. In Cancers including cervical and head and neck squamous cell carcinoma, high pathway activity confers ferroptosis resistance and supports progression, making induction attractive — particularly for mesenchymal and drug-tolerant states that are unusually dependent on GPX4. In neurodegenerative and ischemic disease such as Alzheimer's disease and traumatic brain injury the requirement is the opposite, since pathway failure permits ferroptotic loss of neurons. The axis also intersects broader metabolic signaling, including SIRT1/HIF-1α and AMPK-mediated pathways, positioning it as a hub coordinating responses to oxidative and metabolic stress beyond ferroptosis alone.

Recent Publications Summary

Recent studies have repeatedly implicated the SLC7A11/GPX4 axis in ferroptosis-related disease models, with several interventions reported to suppress ferroptosis by modulating this pathway. In cervical squamous cell carcinoma, baicalin inhibited cell viability, increased reactive oxygen species and malondialdehyde, reduced glutathione, and downregulated NRF2/SLC7A11/GPX4 expression, with ferroptotic mitochondrial changes observed by transmission electron microscopy 42119178May. In traumatic brain injury, corynoxine was reported to inhibit erastin-induced ferroptosis in HT-22 neuronal cells and to improve neuronal damage and cognitive deficits in mice, accompanied by preservation of mitochondrial morphology, reduced oxidative stress, decreased ferrous iron, and upregulation of SLC7A11 and GPX4 in a SIRT1/p53/SLC7A11 mechanism 41935650Apr. In diabetic kidney disease, Yitangkang decoction was investigated through multi-omics analysis as a treatment for glomerular filtration barrier damage, with the study specifically highlighting AMPKα1/ZDHHC8/SLC7A11/GPX4 and TGF-β/Smad signaling pathways 41740333Feb.

Other publications focused on upstream or parallel regulators that converge on SLC7A11 or GPX4 to control ferroptosis sensitivity. In lung cancer, CRL2FEM1B was identified as a heme-responsive E3 ligase that promotes degradation of BACH1, thereby dynamically modulating transcription of ferroptosis-protective genes, particularly SLC7A11; loss of CRL2FEM1B stabilized BACH1, suppressed SLC7A11, and sensitized tumor cells to ferroptosis inducers 42086045May. In head and neck squamous cell carcinoma, TRAPPC4 promoted ferroptosis resistance and tumor progression by reducing TRIM55-mediated GPX4 ubiquitination and degradation, resulting in GPX4 stabilization across multiple experimental models 41974002Apr. In liver cancer, sodium butyrate suppressed proliferation through ferroptosis and apoptosis, with decreased ATF4 and SLC7A11 expression, increased ROS and MDA, reduced glutathione, and mitochondrial dysfunction; these ferroptosis-related changes were reversed by an ATF4 activator 42455831Jul.

Several studies also described direct GPX4-targeting or pathway-associated ferroptosis induction in cancer. A series of phenolato ZrIV complexes, especially compound 1t, showed potent antiproliferative activity against multiple cancer cell lines including cisplatin-resistant Hep G2/DDP cells, with mitochondrial and lysosomal accumulation, excessive ROS generation, lipid peroxidation, mitochondrial membrane depolarization, and GPX4 downregulation consistent with ferroptosis induction 42350927Jun. In addition, quinoa seed extract was reported to attenuate Alzheimer’s disease-like neurodegeneration while targeting the SLC7A11/GPX4 pathway, although the abstract provided only limited mechanistic detail 42171909May.

What Changes, What Holds

1. Pathway-targeted ferroptosis suppression remains a recurring therapeutic theme, but the evidence is still model-specific
REINFORCES Baicalin, corynoxine, and Yitangkang decoction all fit the established account that SLC7A11/GPX4 activity can be manipulated to blunt ferroptosis in disease settings. What changes is not the mechanism but the breadth of recent preclinical support across cancer, brain injury, and kidney disease. The work strengthens the pathway’s status as a therapeutic node, while leaving open how much of this translates beyond the reported models 42119178May41935650Apr.

2. New upstream regulators sharpen the control map without displacing the core axis
REINFORCES CRL2FEM1B, TRAPPC4, and ATF4 add regulatory depth to the already established network governing SLC7A11 and GPX4, but they do not overturn the baseline model that these proteins sit at the center of ferroptosis defense. The main implication is that ferroptosis sensitivity may be tuned at multiple layers, including transcriptional control and GPX4 stability, which could matter for resistance biology in cancer. The mechanistic chain remains preclinical and context-dependent 42086045May41974002Apr.

3. Direct GPX4-linked ferroptosis induction continues to validate the axis as a druggable vulnerability
REINFORCES The ZrIV complexes extend the established idea that suppressing GPX4 activity or expression can drive ferroptosis in cancer cells, including drug-resistant ones. Quinoa seed extract points in the same direction for neurodegeneration, though with limited mechanistic detail. Together, these reports reinforce the pathway as a targetable vulnerability rather than introducing a new biological role, but they do not yet clarify selectivity, in vivo durability, or whether GPX4 downregulation is the dominant causal step 42350927Jun42171909May.

Overview update candidates: none.