PX-478 / Pfizer - LARVOL DELTA

Circadian gene BMAL1 ameliorates renal ischaemia-reperfusion injury in diabetic mice by enhancing mitophagy via the HIF-1/BNIP3 pathway. (PubMed, Sci Rep) - "Inhibition of the Hypoxia-inducible factor-1α (HIF-1α)/ B-cell lymphoma-2 interacting protein 3 (BNIP3) pathway by the HIF-1α inhibitor PX-478 intensified cellular damage and reduced the protective effect of BMAL1 overexpression in TCMK-1 cells. These results indicate that BMAL1 regulates mitophagy in diabetic renal I/RI through the HIF-1α/BNIP3 pathway, providing valuable insights for the development of targeted therapies for diabetic renal I/RI."

Journal • Preclinical • B Cell Lymphoma • Cardiovascular • Diabetes • Diabetic Nephropathy • Lymphoma • Metabolic Disorders • Oncology • Reperfusion Injury • ARNTL • BCL2 • BMAL1 • HIF1A

Local and systemic interactions drive prostatic intraductal carcinoma dissemination. (EACR 2025) - "Hypoxia-inducible factor 1 (HIF1) inhibition was achieved by treatment with PX-478 or by genetic inactivation of Hif1a in PECs... Taken together, our study highlights local and systemic interactions of prostatic epithelial cells that contribute to their metastatic dissemination, and opens novel therapeutic avenues for treatment-resistant and metastatic prostate cancer. (1) Böttcher, R. et al., BMC Cancer 18, 8 (2018) (2) Elfandy, H. et al., Molecular Cancer Research 17, 446–456 (2019) (3) Ci, X. et al., BMC Cancer 24, 744 (2024) (4) Yanushko, D. et al., Cell Death and Disease 16, 46 (2025)"

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • HIF1A • PTEN • TP53

Myeloid cell-specific deletion of EP2 protects against osteoarthritis in mice by Metabolic reprogramming of proinflammatory macrophages (EULAR 2025) - "And Hif-1α inhibitor(PX-478) treatment can reverse the pro-inflammatory effect of PGE2 on M2 macrophages. PGE2-EP2 signal reprogrammed proinflammatory macrophages through a Hif-1α-dependent NF-kB activation manner."

Preclinical • Immunology • Oncology • Osteoarthritis • Pain • Rheumatology • HIF1A • IL4 • IL6 • MMP13 • PTGER2 • PTGER4 • TNFA

Protocatechuic acid suppresses ferroptosis to protect against hypoxic-ischemic encephalopathy by targeting the HIF-1α/VEGFA axis. (PubMed, Phytomedicine) - "In conclusion, PCA confers robust protection against ferroptosis-mediated damage in HIE, with its neuroprotective effects mechanistically linked to the regulation of ferroptosis through the HIF-1α/VEGFA axis in brain microvascular endothelial cells. Moreover, PCA-modified endothelial cell microenvironment ameliorates neuronal damage following injury. These results highlight PCA's therapeutic potential and lay the groundwork for additional translational studies."

Journal • CNS Disorders • HIF1A

Remodelling hypoxic TNBC microenvironment restores antitumor efficacy of Vγ9Vδ2 T cell therapy. (PubMed, Br J Cancer) - "This work underscores that remodelling the hypoxic TNBC microenvironment can restore the antitumor activity of Vγ9Vδ2 T cell therapy. Our findings offer a compelling new adjuvant strategy to improve the outcomes of Vγ9Vδ2 T cell-based therapies for advanced breast cancer treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HIF1A

Hypoxia and HIF-1 inhibition enhance lentiviral transduction efficiency: a novel strategy for gene delivery optimization. (PubMed, BMC Biotechnol) - "Combining hypoxic virus packaging with PX-478 pretreatment synergistically improved transduction efficiency by 20%. These findings suggest that HIF-1 inhibition and controlled hypoxia significantly enhance lentiviral transduction efficiency, establishing a versatile strategy with broad applicability across viral vector-dependent biomedical applications."

Journal • Infectious Disease • HIF1A

HYPOXIA-INDUCED KIT TRANSCRIPTION IN MAST CELLS PLAYS A CRUCIAL ROLE IN INFLAMMATORY BOWEL DISEASE (DDW 2025) - "Hypoxia upregulated KIT expression in mBMMCs and increased TGF-β secretion, both of which were mitigated by the HIF1A inhibitor PX-478...Conclusions Hypoxia-induced chromatin remodeling drives KIT transcription and MC activation in IBD, linking hypoxia to intestinal fibrosis via increased KIT expression and TGF-β secretion. Targeting HIF1A or regulatory elements at the KIT locus could provide novel therapeutic strategies to reduce MC-driven inflammation and fibrosis in IBD."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • HIF1A • IL10 • KIT • TGFB1

Immunodynamic axis of fibroblast-driven neutrophil infiltration in acute pancreatitis: NF-κB-HIF-1α-CXCL1. (PubMed, Cell Mol Biol Lett) - "This study, for the first time, demonstrated that activation of fibroblasts is one of the immunological driving factors for neutrophil infiltration and elucidated that glycolysis driven by the NF-κB-HIF-1α pathway is the intrinsic molecular mechanism by which fibroblasts secrete CXCL1 to chemotactically attract neutrophils. This finding provides a highly promising target for the treatment of AP."

Journal • Inflammation • Pancreatitis • CXCL1 • CXCR2 • HIF1A

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