liproxstatin-1 / Jilin University - LARVOL DELTA

MEGALIN DEFICIENCY EXACERBATES RENAL FIBROSIS DURING THE AKI-TO-CKD TRANSITION AFTER ISCHEMIA–REPERFUSION INJURY VIA THE SELENOPROTEIN P–GPX4–FERROPTOSIS AXIS (ISN-WCN 2026) - "For instance, megalin deficiency attenuates kidney injury in models of rhabdomyolysis-induced AKI and drug-induced nephrotoxicity (e.g., vancomycin), whereas it exacerbates renal injury in models of hemolysis-induced AKI and western diet-induced tubulointerstitial nephritis. Regarding ischemia–reperfusion injury (IRI), megalin mRNA expression decreases 24 hours after IRI and recovers by 96 hours; however, its pathophysiological role during the AKI phase and the AKI-to-CKD transition remains unclear.Methods To elucidate the role of megalin in the AKI and AKI-to-CKD transition after IRI, we used male C57BL/6 mice and tamoxifen-inducible PTEC-specific megalin knockout mice (Megalin fl/fl; Ndrg1-CreERT2; hereafter referred to as iMegKO).First, unilateral IRI (35 min) was performed in C57BL/6 mice to assess the temporal expression and function of megalin...Treatment with the ferroptosis inhibitor liproxstatin-1 or selenium supplementation (sodium selenite) markedly..."

Cardiovascular • Chronic Kidney Disease • Fibrosis • Hematological Disorders • Immunology • Nephrology • Reperfusion Injury • GPX4 • NDRG1 • SELENOP

PANoptosis in Alzheimer's disease: The expanding landscape of programmed cell death mechanisms and therapeutic interventions. (PubMed, Free Radic Biol Med) - "Preclinical studies on compounds like celasterol, magnoflorin, calycosin, and liproxstatin-1, along with clinical trials on the drugs including nicotinamide riboside, barcitinib, dexmeditomidine, and semaglutide, suggest a neuroprotective potential by modulating PANoptotic pathways. This review underscores PANoptosis as a critical pathological mechanism in AD and highlights novel therapeutic avenues aimed at disrupting this cell death program to mitigate AD progression."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • Metabolic Disorders • IGF2BP1 • IRF1 • RIPK1 • STING • ZBP1

Disruption of iron homeostasis by HERC2-FTL axis leads to chondrocyte loss and exacerbates osteoarthritis. (PubMed, Apoptosis) - "ATDC5 chondrocytes were treated with IL-1β or Erastin...In vitro, treatment with the ferroptosis inhibitor Liproxstatin-1 or the HERC2-targeting compound PAC restored redox homeostasis, reduced lipid peroxidation, and improved chondrocyte viability under inflammatory and ferroptosis stress...HERC2 promotes OA progression by activating autophagy-dependent ferroptosis via FTL degradation. Targeting this pathway using ferroptosis inhibitors or HERC2-binding compounds like PAC may offer a promising disease-modifying approach for OA treatment."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • Targeted Protein Degradation • FTL • IL1B

Allogeneic double-negative T cells induce an innate-like cytotoxic function in CD8+T cells against acute myeloid leukemia (AACR 2026) - "Interestingly, a higher CD8DA T-cell signature score in patients' CD8+ T cells correlated with a response to anti-CTLA4 and decitabine treatment. DNTs stimulate an innate-like ability in CD8+ T cells to kill AML in an MHC-independent, DNAM-1-dependent manner through ferroptosis, yielding a potential clinical benefit for patients with AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AIFM2 • CD4 • CD8 • GPX4

Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic opportunities. (PubMed, Front Immunol) - "Therapeutically, promising targeted strategies are highlighted, such as inhaled exosomes loaded with liproxstatin-1, which can selectively inhibit pulmonary ferroptosis without inducing system immunosuppression. By bridging molecular mechanisms to therapeutic innovation, this review outlines a roadmap for precision medicine in COPD, focusing on the ferroptosis-immune axis to disrupt the self-perpetuating cycle of inflammation and tissue damage."

Journal • Review • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • NCOA4

The AhR/ROS-mediated lipid peroxidation pathway contributes to 6PPDQ-induced intestine-specific injury in zebrafish during embryonic development. (PubMed, Fish Shellfish Immunol) - "In support of this finding, both AhR antagonist CH-223191 and ROS scavenger N-acetylcysteine effectively alleviated 6PPDQ-induced intestinal injury, thereby supporting the critical role of 6PPDQ-triggered AhR/ROS signaling in the event...This notion was further reinforced by findings that lipid peroxidation inhibitors, liproxstatin-1 and ferrostatin-1, successfully ameliorated 6PPDQ-induced intestinal injury phenotypes. In summary, our results revealed that the AhR/ROS-mediated lipid peroxidation pathway contributes to the 6PPDQ-caused intestinal injury in zebrafish during embryonic development. These findings provide novel insights into the intestinal susceptibility of 6PPDQ and highlight its potential risks to the embryonic development of fish."

Journal • Inflammation • GPX4 • SLC7A11

Ferroptosis mediates retinal damage caused by the combined effects of sleep deprivation and light damage. (PubMed, Free Radic Biol Med) - "Short-term sleep deprivation exacerbated light-induced retinal injury by promoting ferroptosis, as indicated by disrupted antioxidant capacity, enhanced lipid peroxidation, and disturbed iron homeostasis. Treatment with Lip-1 substantially attenuated these changes."

Journal • Ophthalmology • ACSL4 • AIFM2 • ALOX15 • ANXA2 • GPX4

Nrf2 attenuates diquat-induced renal ferroptosis by regulating mitochondrial ferritin. (PubMed, Toxicol Mech Methods) - "The rats were randomly assigned to four experimental groups: control, diquat, diquat + Liproxstatin-1 (Lip-1, a ferroptosis inhibitor), and diquat + Sulforaphane (SFN, an Nrf2 activator)...Immunofluorescence co-localization analysis further revealed co-localization of Nrf2 and FtMt in kidney tissues. In conclusion, these findings demonstrate that Nrf2 activation attenuates diquat-induced renal ferroptosis by modulating FtMt expression, suggesting that they may serve as a potential therapeutic target for preventing diquat-induced kidney injury."

Journal • Acute Kidney Injury • Nephrology • Renal Disease • ANXA2 • FTH1 • GPX4 • NFE2L2 • SLC7A11

Inhibiting Ferroptosis at 4°C Prolongs Lung Cell Survival for 8 Days - Implications for Donor Lung Preservation (ISHLT 2026) - "Cells were treated with RSL3 (GPX4 inhibitor) and/or liproxstatin-1 (LIP-1, lipid peroxidation inhibitor) (Fig. LIP-1 represents an effective treatment for donor lung preservation. Future work will aim to validate these results in animal models of lung transplantation."

Transplantation • ANXA2 • GPX4

Roles of GPX4 and FSP1 in Esophageal Squamous Cell Carcinoma Treated With Neoadjuvant Chemotherapy. (PubMed, Anticancer Res) - "GPX4 mediates tumor aggressiveness and chemoresistance in NAC-treated ESCC. Persistent GPX4-positivity may serve as a prognostic biomarker, and targeting the GPX4-mediated ferroptosis pathway with standard chemotherapy may overcome resistance in advanced ESCC."

Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • AIFM2 • GPX4

Aspartate treatment ameliorates metabolic dysfunction-associated fatty liver disease through upregulation of CBS and suppression of ferroptosis. (PubMed, J Biol Chem) - "Crucially, pharmacological ferroptosis inhibition (liproxstatin-1) abolished ASP-mediated hepatic improvements, while CBS blockade completely abrogated ASP's therapeutic effects. These findings establish ASP as a novel ferroptosis inhibitor with therapeutic promise for MAFLD."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Long noncoding RNA X-inactive-specific transcript promotes hepatic fibrosis by suppressing ferroptosis in hepatic stellate cells via the miR-663a/GPX4 axis. (PubMed, Front Physiol) - "HSCs were intervened with small interfering RNA against lncRNA-XIST, and Liproxstatin-1 was applied...In vivo, lncRNA-XIST was shown to promote HF progression via the miR-663a/GPX4 axis. LncRNA-XIST promotes HF by acting as a ceRNA for miR-663a, regulating GPX4, and suppressing ferroptosis to activate HSCs."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • COL1A1 • GPX4 • XIST

Ferroptosis in Cerebral Ischemia/Reperfusion Injury: Mechanistic Drivers and Therapeutic Frontiers. (PubMed, Neuropsychiatr Dis Treat) - "Therapeutic strategies target iron chelators (eg, deferoxamine), lipid peroxidation inhibitors (liproxstatin-1), and GPX4 activators to restore redox balance. Targeting propagation mediators (eg, Galectin-13, which reduces SLC7A11 membrane localization) may limit damage spread. Combinatorial therapies addressing iron regulation and lipid peroxidation pathways offer promising neuroprotection against I/R-related neurodegeneration, positioning ferroptosis as a key druggable target."

Journal • Review • Cardiovascular • CNS Disorders • Hematological Disorders • Ischemic stroke • Reperfusion Injury • ACSL4 • AIFM2 • GPX4 • LGALS1 • SLC7A11

Mesaconine alleviates hyperalgesia in CFA-induced mice by modulating YAP1 to suppress cell ferroptosis within the spinal cord. (PubMed, Phytomedicine) - "This study demonstrates that MES suppresses ferroptosis in spinal cord cells by regulating YAP1 activity, thereby reducing neuronal loss, increasing GAD65 expression, and inhibiting neuroinflammation. This restores the central inhibitory effects of the spinal cord, ultimately alleviating hyperalgesia."

Journal • Preclinical • Immunology • Infectious Disease • Inflammation • Mood Disorders • Pain • Rheumatology • YAP1

Neuronal TLR4 upregulation activates the cGAS-STING pathway to induce ferroptosis in EAE mice. (PubMed, Int Immunopharmacol) - "This study proposes a specific TLR4-mtDNA-cGAS-STING-NCOA4 signaling cascade that may facilitate neuronal ferroptosis in EAE mice. These findings suggest a novel mechanism of neuronal injury in MS and underscore that targeting this intrinsic neuronal pathway could represent a promising therapeutic strategy to ameliorate progressive neurodegeneration."

IO biomarker • Journal • Preclinical • CNS Disorders • Hematological Disorders • Immunology • Multiple Sclerosis • GPX4 • NCOA4 • STING • TLR4

Diminazene attenuates astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in Alzheimer's Disease Model. (PubMed, Neuropharmacology) - "These findings indicate that DIZE suppresses astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in AD model."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • MIR10B • NOX4

Targeting HIF-2α in Colorectal Cancer Reveals a Cholesterol Biosynthesis-Dependent Ferroptotic Vulnerability. (PubMed, bioRxiv) - "Targeting this pathway with clinically approved statins (atorvastatin, pitavastatin, simvastatin) synergized with PT2385 to suppress CRC cell growth, reduce colony formation, and enhance cell death...These effects are fully reversed by the ferroptosis inhibitor liproxstatin-1...In vivo, co-administration of PT2385 and atorvastatin significantly reduced tumor growth and increased ferroptotic cell death in xenografts, confirming the mechanistic link. Collectively, these findings uncover a metabolic vulnerability of CRC to dual HIF-2α and cholesterol biosynthesis inhibition, supporting a clinically actionable strategy that leverages safe, FDA-approved statins to potentiate HIF-2α-targeted therapy."

Journal • Colorectal Cancer • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

Nrf2 de-SUMOylation alleviates myocardial ischemia-reperfusion injury (MIRI) by attenuating myocardial ferroptosis in mice. (PubMed, Redox Rep) - "Ferroptosis inhibitor liproxstatin-1 (Lip-1) was used to demonstrate ferroptosis participation in Nrf2 de-SUMOylation regulated MIRI. In vitro, SUMO1/sentrin-specific protease 1 Senp1 KO H9C2 cells were subjected to RSL3-induced ferroptosis to explore underlying mechanism...Mechanistically, Nrf2 de-SUMOylation was associated with a reduction in Transferrin receptor (Tfr) expression level, thereby mitigating ferroptosis in cardiomyocytes. This study highlighted the role of Nrf2 SUMOylation in promoting ferroptosis during MIRI and identified Nrf2 de-SUMOylation as a potential therapeutic target for MIRI."

Journal • Preclinical • Cardiovascular • Coronary Artery Disease • Heart Failure • Myocardial Ischemia • Reperfusion Injury • ANXA2

The research progress of ferroptosis in acute lung injury. (PubMed, Biochem Biophys Rep) - "Its core molecular machinery, including glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and the cystine/glutamate antiporter system Xc-, becomes dysregulated across various ALI subtypes, such as sepsis, ischemia-reperfusion, and COVID-19.This review delineates how ferroptosis contributes to ALI through iron overload, uncontrolled lipid peroxidation, and failure of antioxidant defenses, ultimately leading to pulmonary endothelial and epithelial cell death. We further summarize subtype-specific mechanisms and evaluate emerging therapeutic strategies, including ferroptosis inhibitors (e.g., liproxstatin-1), Nrf2 activators, and iron chelators, highlighting their potential for targeted intervention in ALI/ARDS."

Journal • Review • Acute Lung Injury • Acute Respiratory Distress Syndrome • Cardiovascular • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Reperfusion Injury • Respiratory Diseases • Septic Shock • ACSL4 • GPX4

Methylmercury induces ferroptosis by suppressing GPX4 protein levels in C17.2 mouse neural stem cells. (PubMed, J Toxicol Sci) - "First, we examined the effects of various ferroptosis inhibitors (ferrostatin-1, liproxstatin-1, and deferoxamine) on methylmercury-induced cell death. C17.2 cells overexpressing FLAG-GPX4 exhibited greater resistance to methylmercury than control cells. These results indicate that methylmercury induces ferroptosis in C17.2 cells by suppressing GPX4 protein levels."

Journal • Preclinical • GPX4 • SLC7A11

Ferroptosis in heart failure: from molecular insights to therapeutic implications. (PubMed, Cardiovasc Res) - "It is an abundant form of regulated cell death in the myocardium of many heart failure animal models, including the chronic ischemic, pressure overload, diabetic, septic, obesity-related and doxorubicin-induced cardiomyopathy models...Although definitive causality between ferroptosis and heart failure has not yet been established, emerging evidence suggests that ferroptosis contributes to heart failure progression, supported by multi-layer rescue with classic inhibitors (ferrostatin-1, liproxstatin-1, iron chelators) and by cardiometabolic drugs with clinical efficacy in heart failure (Sodium-Glucose Cotransporter 2 inhibitors, sacubitril/valsartan, finerenone, levosimendan, nicorandil) as well as polyphenols, which restore systolic and/or diastolic indices and reverse remodelling...In this review, through critical synthesis of existing evidence, we analyse current literature, discuss translational barriers and propose a new conceptual mechanistic framework - "the..."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Obesity

Role of Ferroptosis in 2, 4, 6-Trinitrobenzenesulfonic acid Induced Ulcerative Colitis: Targeting Iron Metabolism for Therapeutic Gain. (PubMed, Free Radic Res) - "Small-molecule inhibitors such as Ferrostatin-1 and Liproxstatin-1 effectively reduce mucosal damage and restore antioxidant balance, while iron chelators like deferoxamine alleviate iron overload and ROS generation. Collectively, these findings establish ferroptosis as a pivotal mechanism in TNBS-induced UC, linking oxidative stress and iron dysregulation to mucosal injury. Targeting ferroptosis offers a promising therapeutic avenue for UC management, though further clinical and translational studies are needed to validate its efficacy and safety."

Journal • Review • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • GPX4 • HMOX1

Liproxstatin-1 ameliorates cerebral ischemia-reperfusion injury through inhibiting ferroptosis. (PubMed, Int J Neurosci) - "In vitro experiments further demonstrated that liproxstatin-1 significantly enhanced cell viability and reduced Fe2+ and reactive oxygen species (ROS) levels. Liproxstatin-1 inhibits the process of ferroptosis and alleviates CIRI in rats."

Journal • Cardiovascular • Ischemic stroke • Metabolic Disorders • Reperfusion Injury • ACSL4 • FTH1 • GPX4 • IL17A • TFRC

Limitations of Ferroptosis Inhibitors on the Doxorubicin-Induced Cardiotoxicity. (PubMed, Antioxidants (Basel)) - "In both H9c2 cardiomyocyte cell lines and human induced pluripotent stem cell-derived cardiomyocytes, ferrostatin-1 and liproxstatin-1 rescued cell death induced by RSL3, a ferroptosis inducer, but failed to prevent doxorubicin-induced cell death. Finally, doxorubicin-injected mice treated with ferroptosis inhibitors exhibited significantly reduced survival and increased levels of N-terminal pro B-type natriuretic peptide, a biomarker of heart failure. These findings suggest that inhibiting ferroptosis alone is insufficient to mitigate doxorubicin-induced cardiotoxicity."

Journal • Breast Cancer • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Ferroptosis-driven cryoinjury in porcine testicular tissue: Mechanisms, antioxidant-based cryoprotection, and translational strategies for fertility preservation. (PubMed, Anim Reprod Sci) - "Lipid-directed radical-trapping agents (ferrostatin-1, liproxstatin-1), vitamin-E analogs, selenium (to support GPX4 activity), and iron chelators each reduce post-thaw lipid peroxidation, preserve membrane and mitochondrial integrity, and enhance sperm/SSC performance...Finally, we outline priorities for porcine-specific ferroptosis assays, standardized antioxidant-enriched freezing protocols, dose optimization, and long-term reproductive endpoints. Collectively, the evidence supports a paradigm shift: ferroptosis is a central driver of cryodamage in porcine testicular tissue, and ferroptosis-targeted, antioxidant-based cryoprotection offers a rational path to higher SSC survival, improved graft architecture, and better translational fertility outcomes."

Journal • Preclinical • Review • GPX4