PX-478 / Pfizer - LARVOL DELTA

Suppression of HIF-1α alleviates the symptoms associated with diabetic retinopathy in mice. (PubMed, Exp Eye Res) - "Additionally, PX-478 improved the barrier integrity of BRB in DR mice, and TEM showed an increase in autolysosomes in retinal tissues. This study demonstrates the significant role of HIF-1α in DR pathogenesis, providing a theoretical foundation for further exploration of HIF-1α-directed therapies for this sight-threatening complication of diabetes."

Journal • Preclinical • Cardiovascular • Diabetes • Diabetic Retinopathy • Metabolic Disorders • Retinal Disorders • CDKN1A • HIF1A • MAP1LC3B • PPARG • SIRT1

Low Wall Shear Stress Promotes Atheroma via Arterial Iron Accumulation. (PubMed, Arterioscler Thromb Vasc Biol) - "The use of HIF inhibitors, PX-478 and PT-2385, was able to suppress the exacerbation of atherosclerosis in Apoe-/- mice caused by the endothelial cell-specific knockout of IRP2. Our results indicate that low WSS-induced endothelial cell iron metabolism abnormalities, by inducing arterial wall iron accumulation and abnormal expression of iron metabolism-related proteins, promote the occurrence and development of atherosclerosis. The use of iron chelators can alleviate the onset and progression of low WSS-induced atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Inflammation • APOE

SYNERGISTIC TUMOR IMMUNOTHERAPY VIA CUPROPTOSIS, APOPTOSIS AND CHEMODYNAMIC THERAPY: FUNCTIONAL COPPER(II) COMPLEXES COMBINED WITH HIF-1α INHIBITION (AASLD 2025) - "TEM revealed mitochondrial damage, and apoptosis assays confirmed that Cu4B significantly increased apoptotic cell rates (28.8%) compared to control (2.84%) and cisplatin-treated groups (3.93%), indicating mitochondrial pathway–mediated apoptosis. Cu4B induces ICD in HCC by simultaneously activating cuproptosis, apoptosis, and chemodynamic therapy. Co-administration of PX-478 further amplifies these effects. This work providing a promising strategy for enhancing the efficacy of HCC immunotherapy."

Hepatocellular Cancer • Oncology • Solid Tumor • CALR • DLAT • FDX1 • HIF1A • HMGB1

INDUCTION OF CUPROPTOSIS AND IMMUNOGENIC CELL DEATH BY A NOVEL COPPER CARRIER A3 IN HEPATOCELLULAR CARCINOMA: SYNERGISTIC ENHANCEMENT WITH PX-478 (AASLD 2025) - "A3 induces cuproptosis and ICD in liver cancer cells. Combined with PX-478, it enhances antitumor efficacy with minimal toxicity, offering a promising immunotherapeutic strategy."

Immunogenic cell death • IO biomarker • Hepatocellular Cancer • Liver Cancer • Metabolic Disorders • Oncology • Solid Tumor • DLAT • FDX1 • HIF1A • HMGB1

Bevacizumab and anlotinib combination therapy acts via HIF-1α suppression to exert synergistic anti-angiogenic and anti-tumor effects in non-small cell lung cancer. (PubMed, Front Immunol) - "HIF-1α inhibitor PX478 did not enhance the anti-tumor effects of B+A, but HIF-1α activator DMOG reversed them. In addition, the combination therapy enhanced CD4+ and CD8+ T-cell infiltration and increased pro-inflammatory cytokines. These findings highlight the therapeutic potential of combining anlotinib and bevacizumab for NSCLC treatment and identify HIF-1α as a key target."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • CDH1 • CDH2 • CDH3 • CDH5 • FGFR1 • HIF1A • IL2 • IL6 • PDGFRB • VIM

Jinkui Shenqi pills improve pancreatic islet function in diabetes by modulating macrophage inflammation through the succinate/HIF1α axis. (PubMed, Phytomedicine) - "This study elucidates that JSP mitigates pancreatic β-cell dysfunction by regulating macrophage polarization through the succinate/HIF1α signaling axis. It offers novel insights into the regulatory effects of JSP on energy metabolism."

Journal • Diabetes • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • CD86 • HIF1A • IL10 • IL4 • IL6 • ITGAM • MRC1 • PTPRC • TNFA

Therapeutic potential of Traditional Chinese Medicine Yisui Shengxue pills to inhibit hypoxia-inducible factor-1alpha and general control nonderepressible 2 to regulate the post-chemotherapy immune response: integrating network pharmacology and experimental validation. (PubMed, J Tradit Chin Med) - "YSSX improved MDSC-mediated immunosuppression in a mouse model after chemotherapy by inhibiting the HIF-1α/iNOS-GCN2/eIF2α signaling axis."

Journal • Oncology • CD8 • HIF1A • IFNG • IL12A • TNFA

Luteolin Enhances Anticancer Effects of PX-478 during Hypoxic Response in Metastatic Breast Cancer Cells. (PubMed, Anticancer Agents Med Chem) - "Collectively, our results suggested the combination of luteolin and PX-478 to enhance the anticancer effects of PX-478 in breast carcinoma cells by impeding the cell growth and inducing DNA damage response under hypoxia."

Journal • Breast Cancer • Oncology • Solid Tumor • HIF1A

Shanzhiside methyl ester attenuated cognitive impairment in diabetic mice by inhibiting neuroinflammation and glycolysis via HSP90AA1/HIF1A/STAT1. (PubMed, Phytomedicine) - "SME attenuated cognitive impairment symptom of diabetic mice possibly via HSP90AA1/HIF1A/STAT1 mediated anti-inflammatory and anti-glycolytic effects."

Journal • Preclinical • Alzheimer's Disease • Cognitive Disorders • Diabetes • Inflammation • Metabolic Disorders • CDC37 • HIF1A • HSP90AA1 • STAT1

Isoquercitrin inhibits ferroptosis and ameliorates insulin resistance: Evidence from network pharmacology and in vitro studies. (PubMed, Biochem Biophys Res Commun) - "Moreover, co-treatment with Isoquercitrin and the HIF-1α inhibitor PX-478 further suppressed HIF-1α and HO-1 expression, highlighting Isoquercitrin's involvement in modulating the HIF-1α/HO-1 signaling pathway. These findings suggest that Isoquercitrin may ameliorate IR by inhibiting ferroptosis through regulation of the HIF-1α/HO-1 pathway. This study provides promising prospects for the clinical application of active compounds derived from traditional Chinese herbal medicines in IR treatment."

Journal • Preclinical • Hepatocellular Cancer • Oncology • Solid Tumor • GPX4 • HIF1A • SLC7A11

In situ formed chemo-immunotherapeutic hydrogel for suppression of postoperative glioma recurrence and intraoperative hemostasis. (PubMed, J Control Release) - "Here, we present an innovative in-situ formed fibrin gel-based drug delivery system (PX-478 + αPD-1@Gel), co-loaded with PX-478, a selective hypoxia-inducible factor 1α (HIF-1α) inhibitor, and anti-programmed cell death receptor 1 (αPD-1), for controlled and sequential drug release...Furthermore, the fibrin gel exhibits rapid coagulation and effective hemostasis, reducing intraoperative bleeding and shortening hemostasis time. This dual-functional system, combining localized chemo-immunotherapy with hemostatic properties, shows substantial promise for improving clinical outcomes in glioma patients."

IO biomarker • Journal • Brain Cancer • Glioma • Oncology • Solid Tumor • HIF1A • PD-L1

Astragaloside IV alleviates radiation-induced heart disease by regulating energy metabolism. (PubMed, Phytomedicine) - "Abnormal activation of the HIF-1α/PPARγ axis may represent a potential mechanism underlying X-ray-induced abnormalities in myocardial energy metabolism and cellular damage. Furthermore, AS-IV has the potential to alleviate radiocardiac injury by modulating energy metabolism and restoring mitochondrial function."

Journal • Cardiovascular • Heart Failure • Metabolic Disorders • Oncology • HIF1A • PPARG

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