PX-478 / Pfizer - LARVOL DELTA

Metabolic shifts in the cystic fibrosis mouse small intestine: Potential transcriptional drivers of glycolysis (NACFC 2026) - "Pharmacologic inhibition of HIF1A using the small molecule PX-478 is currently being performed with Seahorse assays and bulk RNA-seq on the treatment groups as endpoints to directly compare HIF1A's effect on glycolysis and assess the transcriptomewide effects of HIF1A inhibition in the small intestine... Our data suggest the HIF1A protein is stabilized through noncanonical pathways and GSH/GSSG ratio assays will show whether there is altered redox balance in the CF intestine, which drives glycolysis in specific intestinal cell types. The lack of this pathway activation in duodenum may stem from the relatively low microbiome influence in the proximal small intestine, in both WT and CF, as DUOX2 is known to be heavily inducible by microbial byproducts. This work will clarify how CF-related metabolic dysregulation occurs at the cellular level and help define the environmental signals, such as oxidative stress, that contribute to disease pathophysiology."

Preclinical • Cystic Fibrosis • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders • Respiratory Diseases • DUOX2 • HIF1A

Hypoxia Confers Ferroptosis Resistance in Glioma Cells via HIF-1α/SREBP1-Mediated Regulation of Lipid Metabolism. (PubMed, J Lipid Res) - "In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies."

Journal • Brain Cancer • CNS Tumor • Glioma • Metabolic Disorders • Oncology • Solid Tumor • FASN • HIF1A • SCD

Effects of exosomes derived from normoxic or hypoxic human umbilical vein endothelial cells on hypoxia-induced cardiomyocyte injury and cardiac fibroblast activation in vitro (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "N-exo derived from HUVECs inhibits while H-exo exacerbates hypoxia-induced AC16 cell injury and RCF activation possibly via the HIF-1α pathway."

Journal • Preclinical • GPX4 • HIF1A • IL1B

Mechanism of Dangua Humai Oral Liquid in ameliorating vascular endothelial injury in type 2 diabetes mellitus via HIF-1α (PubMed, Zhongguo Zhong Yao Za Zhi) - "An animal experiment was carried out for validation, with 36 SPF-grade female SD rats randomized into six groups: normal, model, treatment(Dangua Humai Oral Liquid, 20.5 g·kg~(-1)), inhibitor(PX-478, 2.5 mg·kg~(-1)), combination(Dangua Humai Oral Liquid + PX-478), and metformin(0.142 g·kg~(-1)). Histomorphological analysis revealed severe aortic endothelial damage in the model and inhibitor groups, while all intervention groups showed improved endothelial ultrastructure compared with the model group. Dangua Humai Oral Liquid may protect the vascular endothelium in T2DM by upregulating HIF-1α expression, improving glycolipid metabolism, and reversing vascular endothelial ultrastructural damage."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • HIF1A

HIF-1α in CD4+ T cells drives gout pathogenesis via metabolic reprogramming and Th17 differentiation. (PubMed, J Pharm Anal) - "Both pharmacological inhibition (PX-478) and CD4+ T cell-specific genetic ablation of HIF-1α alleviated gout symptoms, including reduced serum uric acid levels, diminished T helper 17 (Th17) cell polarization, and mitigated renal injury...Seahorse metabolic profiling and 2-deoxy-D-glucose (2-DG) treatment confirmed that HIF-1α promotes gout pathogenesis by driving glycolysis-dependent Th17 expansion and interleukin-17 (IL-17) production...Conversely, HIF-1α activation using 1,1-dimethylethyl ester 6-[2,5-dihydro-5-oxo-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl]-3-pyridinecarboxylic acid (IOX4) exacerbated gout features, which were effectively counteracted by dioscin. Collectively, these findings identify CD4+ T cell-derived HIF-1α as a key glycolytic regulator in gout and highlight dioscin as a promising candidate for HIF-1α-targeted therapeutic intervention."

Journal • Gout • Inflammatory Arthritis • Renal Disease • Rheumatology • CD4 • HIF1A • IL17A

Pan-cancer analysis reveals the prognostic relevance of NUP54 and its association with HIF-1α-related glycolytic phenotypes in lung adenocarcinoma. (PubMed, Cell Signal) - "This NUP54-associated phenotype was attenuated by the HIF-1α inhibitor PX-478 in vitro and in vivo. Overall, this study identifies NUP54 as a potential prognostic biomarker in LUAD and suggests that the NUP54/HIF-1α/glycolysis-related pathway may represent a biological mechanism worthy of further investigation."

Journal • Pan tumor • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Clear Cell Carcinoma • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Gastric Cancer • Glioma • Hepatocellular Cancer • Low Grade Glioma • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • HIF1A • LDHA • PKM • SLC2A1

Astilbin attenuated pyroptosis caused by terbuthylazine-induced histone lactylation in grass carp hepatocytes. (PubMed, Ecotoxicol Environ Saf) - "Therefore, we treated L8824 cells with siMETTL14, NAC, PX-478, 2-DG, DMOG or Oxamate to achieve it...Molecular docking analysis and CETSA revealed a binding interaction between AST and METTL14. In summary, this study revealed that AST inhibits METTL14-mediated m6A methylation of FOXO1 to maintain redox homeostasis, thereby suppressing histone lactylation and ultimately attenuating pyroptosis in L8824 cells."

Journal • Hepatology • Liver Failure • HIF1A • METTL14

Botulinum toxin type E alleviates trigeminal neuropathic pain via modulation of the HIF-1α-NLRP3 pathway. (PubMed, Front Toxicol) - "Intraganglionic injection of PX-478, a HIF-1α inhibitor, similarly attenuated mechanical allodynia, downregulated NLRP3 expression, and decreased IL-1β, IL-18, TNF-α, and IL-6 levels in the iTG. Collectively, these findings demonstrate that modulation of the HIF-1α-NLRP3 pathway in the iTG plays a critical regulatory role in neuropathic pain development and suggest that BoNT/E may serve as a promising therapeutic strategy for managing chronic neuropathic pain."

Journal • Neuralgia • Oncology • Pain • HIF1A • IL18 • IL1B • IL6 • NLRC5 • NLRP3 • TNFA

Molecular understanding for therapeutic targeting of hypoxia in breast cancer. (PubMed, Expert Opin Ther Targets) - "Apart HIF itself, other potential molecular targets such as prolyl-hydroxylases (PHD), von Hippel-Lindau protein (VHL), monocarboxylate transporters (MCTs), Na+ /H+ exchangers (NHEs), vacuolar ATPases (V-ATPase), anion exchangers (AEs), Na+ /HCO₃- co-transporters (NBCs), vascular endothelial growth factor (VEGF) and carbonic anhydrases were identified as being involved in tumorigenesis. HIF-1α inhibitors (topotecan, digoxin, PX-478), hypoxia-activated prodrugs (evofosfamide, apaziquone, porfiromycin, tirapazamine, banoxantrone) and carbonic anhydrase IX/XII inhibitors (SLC-0111) are either used clinically or in clinical development for the management of hypoxic breast cancers."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome • CA9 • HIF1A

Lactylation of HIF-1α at K172 drives HIF-1 complex assembly to promote hypoxia-induced immune evasion in esophageal squamous cell carcinoma. (PubMed, Cancer Lett) - "Functionally, reducing hypoxia with the agents TH-302 or PX-478 in the AKR model enhanced intratumoral CD8+ T cell infiltration and increased their expression of Granzyme B, IFNγ, and TNFα. Furthermore, in a preclinical ESCC model, pharmacological inhibition of HIF-1α with PX-478 synergized with anti-PD-1 therapy, leading to superior tumor control and enhanced CD8+ T cell cytotoxicity. Our study identifies HIF-1α K172 lactylation as a pivotal mechanism of hypoxia-mediated immune escape in ESCC, suggesting a therapeutic strategy to improve immunotherapy."

IO biomarker • Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CD8 • GZMB • HIF1A • IFNG • TNFA

Qinggan Lidan Capsule Attenuates Acetaminophen-Induced Liver Injury by Inhibiting the HIF-1α Signaling to Alleviate Mitochondrial Damage-Triggered Hepatocyte Apoptosis. (PubMed, J Ethnopharmacol) - "These findings demonstrate that QGLDC alleviates hepatocyte apoptosis triggered by APAP-induced mitochondrial damage through inhibiting the aberrant activation of the HIF-1α signaling. This study underscores the promising therapeutic potential of QGLDC for mitigating DILI and provides a compelling rationale for its clinical development."

Journal • Hepatology • Inflammation • Liver Failure • HIF1A

HIF-1α pathway is a therapeutic vulnerability in mucinous colorectal cancer (AACR 2026) - "Immunohistochemical and spatial transcriptomic analyses confirmed marked elevation of HIF-1α protein and target gene expression in murine and patient-derived mucinous CRC models compared to non-mucinous counterparts.Functionally, pharmacologic inhibition of HIF-1α using PX-478 completely prevented mucinous tumor formation in the genetically engineered mouse models, restoring normal crypt architecture and markedly extending survival...Collectively, these findings identify HIF-1α as a molecular dependency and therapeutic vulnerability in muCRC. Together, these results provide a strong translational rationale for HIF-targeted therapy in mucinous and related serrated CRC subtypes."

Colorectal Cancer • Oncology • Solid Tumor • HIF1A • MUC2 • SPDEF • TFF3

Downregulation of PDLIM2 promotes tumor growth through regulation of oncometabolites and HIF-1α pathway (AACR 2026) - "To further validate this axis, we performed an in vivo study with cancer animal model using PX-478, an orally bioavailable HIF-1α inhibitor...Collectively, these findings highlight a novel regulatory link between PDLIM2, mitochondrial metabolism, and HIF-1α signaling in lung cancer. They emphasize the tumor-promoting effects of PDLIM2 downregulation and suggest that therapeutic inhibition of HIF-1α may represent a promising precision strategy for patients with PDLIM2-deficient tumors."

Lung Cancer • Oncology • Solid Tumor • HIF1A

Investigating PLOD2 as a therapeutic target to overcome metastasis in radiorecurrent prostate cancer (AACR 2024) - "Treatment with PX-478 reduced both HIF1α and PLOD2 protein expression, and significantly reduced invasion, migration, and in vivo extravasation in DU145-CF cells, thereby indicating its potential as a pharmacological inhibitor of HIF1α-associated PLOD2 in radiorecurrent PCa. Together, our results demonstrate for the first time the role of PLOD2 in radiorecurrent PCa invasiveness, and point towards its potential as a therapeutic target to reduce metastasis and improve survival outcomes in PCa patients."

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

Uremic toxin p‑cresyl sulfate enhances the calcification of aortic valvular interstitial cells via klotho/sirtuin‑1 signaling. (PubMed, Mol Med Rep) - "The present study demonstrated that PCS induced VIC calcification by activating HIF‑1α signaling and downregulating klotho. Treatment with klotho or SRT1720 was shown to attenuate PCS‑mediated activation of the NF‑κB/RUNX2 signaling pathway, suggesting that these agents demonstrate notable therapeutic potential for targeting PCS‑induced CAVD."

Journal • Cardiovascular • Chronic Kidney Disease • Heart Failure • Inflammation • Nephrology • Renal Disease • HIF1A • KL • RUNX2 • SIRT1

Oxidative Stress Mediated by Macrophages Promotes Angiogenesis and Early Development of Endometriosis. (PubMed, Antioxidants (Basel)) - "Since HIF-1α is an important trigger of neoangiogenesis, we further administered a HIF-1α-specific inhibitor (PX-478) to our endometriotic model and further confirmed the same effects on the lesions. Taken together, these data suggest that an intact Alox15 pathway and HIF-1α signaling may play important roles in the macrophage-mediated oxidative stress and neovascularization of endometriosis in the early stages, suggesting anti-inflammation and antioxidation as potential therapeutic targets for the development of endometriosis."

Journal • Endometriosis • Gynecology • Infertility • Inflammation • Musculoskeletal Pain • Pain • Sexual Disorders • Women's Health • ALOX15 • HIF1A

Hypoxia‑induced miR‑135b‑5p promotes neuroendocrine differentiation of prostate cancer cells through HIF1AN‑HIF1α axis. (PubMed, Oncol Rep) - "Furthermore, pharmacological inhibition of HIF1α using PX‑478 abrogated hypoxia‑induced NED and attenuated activation of AKT/mTOR signaling, further underscoring the significance of the miR‑135b‑5p‑HIF1AN‑HIF1α axis in NED of PCa cells. Collectively, the findings of the present study reveal a novel miR‑135b‑5p‑HIF1AN‑HIF1α signaling axis that is involved in hypoxia‑induced NED via AKT/mTOR activation and identify miR‑135b‑5p and HIF1α as potential therapeutic targets for NEPC."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • HIF1A • MIR135B

Dual phase modeling of Chrysotile carcinogenesis from 3D cell transformation to orthotopic tumors. (PubMed, Sci Rep) - "In this investigation, we established a novel NIH/3T3 cell model of asbestos-induced malignant transformation using 3D culture techniques, followed by the development of a corresponding mouse model via orthotopic transplantation. Subsequent administration of the HIF-1α inhibitor PX-478 to both models allowed for the assessment of model reliability through the observation of malignant phenotypes and associated protein alterations."

Journal • Oncology • Transplantation • HIF1A

Icariin sensitizes glucocorticoid therapy in doxorubicin-induced fibrotic nephrotic syndrome via the HIF-1α/NF-κB/HDAC2 Axis. (PubMed, Int Immunopharmacol) - "We established a doxorubicin (DOX)-induced rat model featuring tubular epithelial injury with epithelial-to-mesenchymal transition (EMT), interstitial fibrosis, and a blunted therapeutic response to prednisone (Pred). PX-478 recapitulated key components of this response. Collectively, these data implicate a tubulointerstitial HIF-1α/NF-κB/HDAC2 axis as a key contributor to blunted GC responsiveness in fibrotic NS and support ICA as a microenvironment-targeted adjunct to enhance GC efficacy."

Journal • Fibrosis • Glomerulonephritis • Immunology • Inflammation • Nephrology • Renal Disease • HDAC2 • HIF1A • NR3C1

Mitochondrial retrograde signaling initiates HIF-1α/BNIP3/NIX-mediated mitophagy in Tibetan high-altitude adaptation. (PubMed, Cell Death Discov) - "Furthermore, treatment with N-acetylcysteine (NAC), PX-478, or Mdivi-1 significantly attenuated BNIP3/NIX-mediated mitophagy, leading to an aggravation of mtDNA-mediated inflammation and apoptosis in M9a+shEPAS1 cells during hypoxia. This study first reveals that ROS-driven HIF-1α-BNIP3/NIX-mediated mitophagy mitigates hypoxia-induced inflammation and apoptosis, contributing to the enhanced hypoxia adaptation observed in Tibetans. HIF-1α-BNIP3/NIX-mediated mitophagy may offer potential therapeutic targets for high-altitude illnesses by regulating cellular energy metabolism and inflammation."

Journal • Inflammation • EPAS1 • HIF1A

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