New research reveals that lactate-driven histone H3K18 lactylation activates a PSRC1/AKT/HIF-1α positive feedback loop that propels the malignant progression of Wilms tumor, the most common childhood

Read the full paper: HIF-1α-driven lactate from mesenchymal stem/stromal cells reprograms monocyte metabolism and suppresses autoimmune uveoretinitis

Read the full paper: Acetylcholine enhances HIF-1α signaling in pancreatic cancer cells under hypoxia through the nAChR-α7/PDPK1/YAP pathway

Clear cell renal cell carcinoma (ccRCC) is largely driven by the transcription factor hypoxia-inducible factor 2α (HIF-2α)1. Here we show that monotherapy with casdatifan—an orally bioavailable, potent and selective HIF-2α inhibitor2—produces meaningful, durable antitumour activity with manageable safety in individuals with refractory metastatic ccRCC. Dose-expansion data from the ARC-20 study ( NCT05536141 ) are presented, including for the 100 mg once daily (QD) cohort (n = 32) and the total cohort (n = 127). Treatment discontinuation from casdatifan-related adverse events was infrequent (3%), and class-effect toxicities included anaemia and hypoxia. The confirmed objective response rates (ORRs) were 35% (95% confidence intervals (CI) = 19–55%; 100 mg QD) and 31% (95% CI = 23–40%; total); median progression-free survival (PFS) was not estimable (95% CI = 5.7–not estimable; 100 mg QD) and 12.2 months (9.4–20.6; total). Greater maximal reductions in serum

Read the full paper: CCN1 upregulation in diabetic wounds suppresses PINK1/Parkin-mediated mitophagy in dermal fibroblasts by regulating HIF-1α protein stability under decompensated hypoxic conditions

Hypoxia is not simply harmful or protective. Recent studies suggest that hypoxia-inducible factor 1-alpha (HIF-1α) acts as a time- and context-sensitive regulator of tissue-state transitions. We propose that transient HIF-1α activity enables regenerative entry, whereas persistent or unresolved signalling promotes maladaptive remodelling, degeneration, and ageing.

Hypoxia is not simply harmful or protective. Recent studies suggest that hypoxia-inducible factor 1-alpha (HIF-1α) acts as a time- and context-sensitive regulator of tissue-state transitions. We propose that transient HIF-1α activity enables regenerative entry, whereas persistent or unresolved signalling promotes maladaptive remodelling, degeneration, and ageing.

Obstructive sleep apnea (OSA) is a prevalent chronic respiratory condition characterized by repetitive upper airway collapse during sleep, leading to transient hypoxemia and arousals from sleep. Multiple risk factors heighten susceptibility to OSA. Intermittent hypoxia caused by OSA can increase the risk of end-organ morbidity. Key mechanisms include mitochondrial dysfunction, excessive production of ROS, and inflammation driven by NF-κB. HIF-1α responses vary by tissue and exposure pattern and may be attenuated during chronic intermittent hypoxia.

TNF-driven metabolic reprogramming enhances glucose utilization in monocytes through inducible nitric oxide synthase (iNOS) and hypoxia-inducible factor 1α (HIF-1α), promoting parasite control and host...

Obstructive sleep apnea (OSA) is a prevalent chronic respiratory condition characterized by repetitive upper airway collapse during sleep, leading to transient hypoxemia and arousals from sleep. Multiple risk factors heighten susceptibility to OSA. Intermittent hypoxia caused by OSA can increase the risk of end-organ morbidity. Key mechanisms include mitochondrial dysfunction, excessive production of ROS, and inflammation driven by NF-κB. HIF-1α responses vary by tissue and exposure pattern and may be attenuated during chronic intermittent hypoxia.

Neuropathic pain involves spinal microglial activation and metabolic changes.Forsythoside B (FB) has anti-inflammatory effects, but its role in neuropathic pain and microglial glycolysis remains unclear. We investigated the effects and mechanisms of FB in mice with chronic constriction injury (CCI) and in LPS-stimulated BV2 microglia.FB reduced mechanical allodynia and thermal hyperalgesia in CCI mice. FB also reduced the spinal levels of HIF-1, HK2, PKM2, LDHA, and CD86. It decreased the proportion of IBA1+/CD86+ cells and the levels of IL-1{beta}, IL-6, and TNF-. In LPS20 stimulated BV2 microglia, FB reduced glycolysis-related proteins, proinflammatory markers, and cytokine release. FB also reduced glycolytic activity and partly restored basal mitochondrial respiration. FB did not change Hif1a mRNA levels. However, it Manuscript Click here to access/download;Manuscript;Manuscript.docx increased HIF-1 ubiquitination and promoted its proteasome-dependent degradation. HIF-1 overexpression partly reversed the effects of FB on glycolytic enzymes, CD86 expression, and proinflammatory cytokine production. Immunoprecipitation followed by mass spectrometry and UbiBrowser analysis identified USP7 as a candidate HIF27 1-associated deubiquitinase. Molecular docking and cellular thermal shift assays supported a possible interaction between FB and USP7. FB reduced the association between USP7 and HIF-1. USP7 knockdown produced effects similar to those of FB on HIF-1 ubiquitination and downstream glycolytic and inflammatory responses.Overall, FB alleviated neuropathic pain and reduced proinflammatory microglial responses. These effects may involve the promotion of HIF-1 degradation through modulation of the USP7-HIF-1 regulatory axis.

TNF-driven metabolic reprogramming enhances glucose utilization in monocytes through inducible nitric oxide synthase (iNOS) and hypoxia-inducible factor 1α (HIF-1α), promoting parasite control and host...

Spinal cord injury (SCI) often results in severe hypoxia and excessive activation of neuroinflammation, which aggravates neuropathology and neurological dysfunction. D-dopachrome tautomerase (D-DT), the homolog of macrophage migration inhibitory factor (MIF), is a key proinflammatory mediator implicated in inflammatory diseases of multiple tissues. However, its relation with hypoxia and the potential impact on neuroinflammation following SCI remain elusive. Herein, the dynamic expression of D...

Zhou et al. identify ellagic acid (EA) as an allosteric inhibitor of YTHDF proteins that binds to a conserved site shared across YTHDF family members. By disrupting YTHDF2-mediated RNA decay, EA stabilizes PFKFB4 mRNA to prevent HIF-1α degradation and upregulates BNIP3 expression, thereby driving triple-negative breast cancer cell death.

Read the full paper: Allosteric modulation of YTHDFs by ellagic acid suppresses triple-negative breast cancer via non-canonical activation of the HIF-1α pathway

We identify ellagic acid (EA) as a compound that binds to YTHDF proteins and disrupts their interaction with N6-methyladenosine (m6A)-modified RNAs.

Read the full paper: Hypoxia Promotes Pancreatic Cancer Malignancy via HIF-1α-induced Doublecortin-like Kinase 1 Upregulation