PX-478 / Pfizer - LARVOL DELTA

The hypoxic microenvironment of Candida albicans biofilms shapes neutrophil responses. (PubMed, Front Immunol) - "To assess the role of hypoxia signaling in neutrophil responses, cells were treated with the selective HIF-1α inhibitors LW6 and PX478...These findings provide novel insights into the impact of biofilm-induced hypoxia on neutrophil responses, identifying HIF-1α as a key regulator of immune adaptation in fungal biofilms. Targeting hypoxia pathways may offer new therapeutic strategies to modulate neutrophil responses and enhance host defenses against fungal infections."

Journal • Infectious Disease • CASP3 • CASP7 • CCL4 • CXCL8 • ELANE • HIF1A • MCL1

Bidirectional modulation of glycolysis using a multifunctional nanocomposite hydrogel promotes bone fracture healing in type 2 diabetes mellitus. (PubMed, Bioact Mater) - "To further regulate the inflammatory microenvironment, we incorporated nanoparticles loaded with PX-478, a HIF-1α specific inhibitor, into the hydrogel, with folic acid covalently modified to target proinflammatory M1 macrophages...Comprehensive in vitro and in vivo experiments in a T2D fracture mouse model confirmed the hydrogel's ability to improve the inflammatory microenvironment and accelerate bone healing. Our findings underscore the therapeutic potential of targeting cellular glycolysis as a promising approach for enhancing fracture healing in diabetic patients."

Journal • Diabetes • Inflammation • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Type 2 Diabetes Mellitus • HIF1A

Role of Hypoxia-Inducible Factors in Respiratory Syncytial Virus Infection-Associated Lung Disease. (PubMed, Int J Mol Sci) - "This study aimed to characterize the disease-modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α PT2385 inhibitors in RSV-infected BALB/c mice. The analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers for each HIF inhibitor. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of compounds currently in use or under therapeutic consideration."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • EPAS1 • HIF1A

Iguratimod modulates osteoclast differentiation in rheumatoid arthritis: Insights into AMPK/HIF-1α signaling pathway regulation. (PubMed, Tissue Cell) - "Iguratimod potentially modulates AMPK/HIF-1α pathway, thereby suppressing release of inflammatory factors and influencing differentiation of peripheral blood osteoclasts in RA patients. These findings suggest promising therapeutic strategies for exposure of joint deformities associated with RA."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CCL20 • CTSK • CXCL8 • HIF1A • IL17A • IL6 • MMP9 • TNFA

Unraveling the role of HIF-1α in allergic rhinitis: A key regulator of epithelial barrier integrity via PI3K pathway. (PubMed, Tissue Cell) - "HIF-1α aggravates AR by promoting inflammation, mucosal remodeling, and epithelial barrier dysfunction via PI3K pathway activation. This finding not only enriches our understanding of AR pathophysiology but also highlights HIF-1α and its downstream signaling pathways as prospective therapeutic targets for AR."

Journal • Allergic Rhinitis • Immunology • Inflammation • Otorhinolaryngology • HIF1A • IL13 • TJP1

Baicalin-Geniposide combination modulates microglia polarization against chronic cerebral ischemia and concomitant kidney injury via the HIF-1α/EPO/NF-κB pathway. (PubMed, J Neuroimmunol) - "BC/GD alleviated cerebral and kidney inflammatory injury, and its mechanism may be related to the modulation of microglia polarization through HIF-1α/EPO/NF-κB."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Nephrology • Renal Disease • HIF1A • TNFA

Macrophage HIF-1a inhibition alleviates inflammation-induced acute liver failure in mice (APASL 2025) - "Our data suggest that PX-478 administration leads to HIF-1α inhibition and decreased IL-1β secretion in macrophages, which represents a promising therapeutic strategy for inflammation-induced ALF. Table and Figure:Figure 1.PX-478 combined with TNFα neutralizing antibody treatment improves ALF synergistically Figure 2.PX-478 protects againstinflammation-induced acute liver failure"

Preclinical • Anesthesia • Hepatology • Inflammation • Liver Failure • Oncology • HIF1A • IL1B • IL1R1 • TNFA

Unraveling the crucial role of SDF-1 in osteoarthritis progression: IL6/HIF-1α positive feedback and chondrocyte ferroptosis. (PubMed, Int Immunopharmacol) - "SDF-1 mediates chondrocyte ferroptosis via the IL6/HIF-1α positive feedback, promoting OA."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • ACSL4 • COL2A1 • CXCL12 • GPX4 • HIF1A • IL6 • MMP13 • SLC7A11

Arctiin attenuated NASH by inhibiting glycolysis and inflammation via FGFR2/CSF1R signaling. (PubMed, Eur J Pharmacol) - "HIF1A was proved to be involved in this process using HIF1A agonist DEF and HIF1A inhibitor PX478. Molecular docking and molecular dynamic suggested that ARC might combine with FGFR2. In conclusion, the present study demonstrated that ARC ameliorated NASH by inhibiting glycolysis and inflammation via FGFR2/CSF1R signaling."

Journal • Hepatology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • CSF1R • FGFR2 • HIF1A

Hypoxia-inducible factor 1α inhibitor reduces hippocampal neuronal ferroptosis. (PubMed, Neural Regen Res) - "It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway. In summary, these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway, alleviating oxidative stress, and reducing ferroptosis in hippocampal neurons."

Journal • CNS Disorders • Epilepsy • CAT • HIF1A • HMOX1

Golgi condensation causes intestinal lipid accumulation through HIF-1α-mediated GM130 ubiquitination by NEDD4. (PubMed, Exp Mol Med) - "Furthermore, the HIF-1α inhibitor PX-478 prevents Golgi condensation, which decreases lipid accumulation and promotes high-density lipoprotein secretion in high-fat-diet-fed mice. Overall, our results suggest that Golgi condensation plays a key role in lipid trafficking in the small intestine through the HIF-1α- and NEDD4-mediated degradation of GM130, and these findings highlight the possibility that the prevention of structural modifications in the Golgi apparatus can ameliorate intestinal lipid accumulation in obese individuals."

Journal • Obesity • Targeted Protein Degradation • APOA1 • HIF1A • NEDD4

Lactate Promotes Hypoxic Granulosa Cells' Autophagy by Activating the HIF-1α/BNIP3/Beclin-1 Signaling Axis. (PubMed, Genes (Basel)) - "These findings unveil a novel mechanism by which hypoxia regulates GC autophagy through lactate production, highlighting its potential role in sustaining follicular development under hypoxic conditions."

IO biomarker • Journal • BCL2 • BECN1 • BNIP3 • HIF1A • LDHA • LDHB

Integrating Ultrabright Polymer Dots and Stereo NIR-II Imager for Assessing Anti-Angiogenic Drugs in Oral Cancer Model. (PubMed, J Cell Mol Med) - "Furthermore, PX-478 could suppress the expression of HIF-1α and vascular endothelial growth factor-A (VEGF-A), but BPRC0261 only suppressed VEGF-A. Taken together, this innovative 3D NIR-II imaging system combining the biocompatible Pdots with unique optical specificity enables non-invasive, real-time monitoring the efficacy of anti-angiogenic compounds."

Journal • Preclinical • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Tongue Carcinoma • CD31 • HIF1A • PECAM1

Hypoxia Reduces Mouse Urine Output via HIF1α-Mediated Upregulation of Renal AQP1. (PubMed, Kidney Dis (Basel)) - "Furthermore, the upregulation of AQP1 by hypoxia and roxadustat can be blocked by the HIF1α inhibitor PX-478 in mPTCs. This study demonstrates that hypoxia can reduce the urine volume of mice via upregulating AQP1 expression by HIF1α in the proximal tubular epithelial cells. Our findings also suggest a potential mechanism involved in water metabolism disorders in patients with AMS and in patients with CKD receiving roxadustat treatment."

Journal • Preclinical • Chronic Kidney Disease • Hematological Disorders • Metabolic Disorders • Nephrology • Renal Disease • AQP1 • EPAS1 • HIF1A

Spring viremia of carp virus infection induces hypoxia response in zebrafish by stabilizing hif1α. (PubMed, J Virol) - "Additionally, treatment with the HIF1α-specific inhibitor PX478 enhanced the antiviral ability against SVCV infection in zebrafish and zebrafish cells. Our findings not only reveal a relationship between SVCV infection and the hypoxia signaling pathway in fish but also provide a strategy for reducing the damage of viral disease in the aquaculture industry."

Journal • Infectious Disease • Targeted Protein Degradation • HIF1A

PX-478 induces apoptosis in acute myeloid leukemia under hypoxia by inhibiting the PI3K/AKT/mTOR pathway through downregulation of GBE1. (PubMed, Biochem Pharmacol) - "Re-expression of GBE1 in shGBE1 cells alleviated apoptosis and reduced PX-478- induced apoptosis and pathway downregulation. In conclusion, our findings provide convincing evidence that PX-478 induces apoptosis by inhibiting the PI3K/AKT/mTOR pathway through downregulation of GBE1 in AML cells."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • HIF1A

The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse. (PubMed, J Obstet Gynaecol) - "It reduces vaginal length, attenuates fibrosis, and modulates collagen synthesis. Its immunomodulation is evident through reduced M1 and M2 macrophages and suppressed IL-18 secretion."

Journal • Preclinical • Fibrosis • Immunology • Inflammation • CD80 • HIF1A • IL18 • MMP2 • MMP9 • MRC1 • TIMP1 • VIM

The impact of X-rays on cardiac hydrometabolism and the regulatory role of AS-IV. (PubMed, Int Immunopharmacol) - "Aberrant activation of the HIF-1α/AQPs/Cx43 axis is a key mechanism in X-ray-induced cardiomyocyte edema and damage. AS-IV can ameliorate X-ray induced cardiac damage by regulating hydrometabolism."

IO biomarker • Journal • Cardiovascular • Fibrosis • Heart Failure • AQP1 • BAX • BCL2 • CASP3 • HIF1A

Aquaporin-1 Facilitates Macrophage M1 Polarization by Enhancing Glycolysis Through the Activation of HIF1α in Lipopolysaccharide-Induced Acute Kidney Injury. (PubMed, Inflammation) - "Furthermore, the suppression of HIF1α with PX-478 led to decreased expression levels of Hexokinase 2 (HK2) and Lactate Dehydrogenase A (LDHA), indicating that AQP1 regulates glycolysis through HIF1α...Inhibition of the glycolytic process not only weakened M1 polarization but also promoted M2 polarization, thereby reducing the release of inflammatory cytokines. These findings provide a novel perspective for developing therapeutic strategies that target AQP1 and HIF1α, potentially improving the treatment of sepsis-associated AKI."

Journal • Acute Kidney Injury • Infectious Disease • Nephrology • Renal Disease • Septic Shock • AQP1 • HIF1A • HK2 • IL10 • IL6 • LDHA • TNFA

PX-478 Alleviated the Autism Spectrum Disorder Progression of Offspring Rats Induced by Prenatal Hypoxia. (PubMed, J Integr Neurosci) - "The findings suggest that PX-478 treatment attenuated autism-like behavior in offspring. HIF-1α might play an important role in autism-like behavior induced by prenatal hypoxia, which may be realized by inhibiting PTEN activity."

Journal • Preclinical • Autism Spectrum Disorder • Genetic Disorders • Mood Disorders • Psychiatry • HIF1A • PTEN

Fetal hypoxia exposure induced Hif1a activation and autophagy in adult ovary granulosa cells. (PubMed, Biol Reprod) - "We then treated GCs isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif-1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary."

Journal • Metabolic Disorders • Oncology • Ovarian Cancer • HIF1A

Targeting PLOD2 suppresses invasion and metastatic potential in radiorecurrent prostate cancer. (PubMed, BJC Rep) - "Prostate cancer cell lines were treated with siRNA, or the drug PX-478 prior to in vitro invasion, migration, or in vivo chick embryo (CAM) extravasation assay...Finally, the long non-coding RNA LNCSRLR acts as a promoter of invasion downstream of PLOD2. Together, our results demonstrate for the first time the role of PLOD2 in radiorecurrent prostate cancer invasiveness, and point towards its potential as a therapeutic target to reduce metastasis and improve survival outcomes in prostate cancer patients."

Journal • Metastases • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • HIF1A • PLOD2

The 'ABC' of split-nanoluciferase HIF heterodimerization bioassays: Applications, benefits & considerations. (PubMed, Biochem Pharmacol) - "This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols."

Journal • Hematological Disorders • Oncology • HIF1A

Exosomal circ-0100519 promotes breast cancer progression via inducing M2 macrophage polarisation by USP7/NRF2 axis. (PubMed, Clin Transl Med) - "Our study revealed that exosomal circ-0100519 is a potential biomarker for BC diagnosis and prognosis, and the HIF-1α inhibitor PX-478 may provide a therapeutic target for BC."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Women's Health • HIF1A • USP7

Heyingwuzi formulation alleviates diabetic retinopathy by promoting mitophagy via the HIF-1α/BNIP3/NIX axis. (PubMed, World J Diabetes) - "HYWZF alleviated DR and associated damage by promoting mitophagy via the HIF-1α/BNIP3/NIX axis."

IO biomarker • Journal • Diabetes • Diabetic Retinopathy • Metabolic Disorders • Retinal Disorders • BCL2 • BNIP3 • BNIP3L • HIF1A • PTEN