Search Results (835)

Tumour hypoxia significantly influences disease advancement and treatment resistance in oral squamous cell carcinoma (OSCC). Hypoxia-inducible factor-1α (HIF-1α) is preserved when oxygen is lacking and triggers the expression of hypoxia-responsive genes that have roles in angiogenesis, metabolic adaptability, tumour cell viability, invasion, and metastasis. The elevated levels of vascular endothelial growth factor (VEGF) induced by HIF-1α result in atypical angiogenesis. The dysfunction of cell junction proteins and heightened activity of matrix metalloproteinases caused by hypoxia facilitate cancer invasion and metastasis. Hypoxic stress prompts cellular modifications, including autophagy and the preservation of cancer cell populations with enhanced survival capabilities, hence facilitating tumour recurrence and heterogeneity. Hypoxia diminishes the effectiveness of standard chemotherapy and radiotherapy due to decreased drug transport, hindered cell growth, and diminished oxygen-dependent radiation-induced DNA damage. Thus, treatment strategies for the hypoxic tumour microenvironment encompass the suppression of HIF and VEGF, tumour reoxygenation, hypoxia radiosensitizers, and hypoxia-activated lethal compounds. Nonetheless, the diverse and fluctuating characteristics of tumour hypoxia, along with the initiation of compensatory survival mechanisms, continue to pose significant obstacles. Enhanced comprehension of hypoxia-induced molecular networks and the advancement of multimodal, biomarker-directed treatment strategies could improve outcomes in OSCC. Full article

Successful embryo implantation requires intimate crosstalk between the blastocyst and the uterine epithelium within a defined window of receptivity. However, the metabolic signals that mediate this process in mammals remain poorly understood. In this study, pregnant mice, primary uterine cell culture and uterine epithelial organoids were used to examine the regulation and function of heme oxygenase-1 (HO-1) during mouse embryo implantation and decidualization. We demonstrate that embryo-derived lactic acid drives heme catabolism and regulates epithelial receptivity in mice through a hypoxia-inducible factor 1α (HIF1α) -heme oxygenase-1 (HO-1) signaling axis. Specifically, lactic acid stabilizes HIF1α to induce HO-1 expression in uterine epithelial cells by promoting von Hippel-Lindau (VHL) nucleolar sequestration and downregulating PHD2/3. Additionally, lactic acid suppresses the transcriptional repressor BACH1, further facilitating HO-1 induction. At physiological heme levels, HO-1-derived bilirubin promotes epithelial receptivity by increasing phosphorylated STAT3 (p-STAT3) and downregulating MUC1. A low dose of hemin promotes epithelial receptivity and decidualization, whereas a high dose of hemin suppresses these processes. Pharmacological inhibition of HO-1 in mice markedly reduces implantation sites, establishing the functional necessity of this pathway. However, when heme levels exceed the regulatory capacity of HO-1, epithelial dysfunction ensues, characterized by reduced p-STAT3 and elevated MUC1, which ultimately disrupts implantation. Consistent with this, chronic heme exposure by oral gavage in mice increases uterine heme levels and upregulates BACH1, thereby suppressing HO-1 and trapping the uterus in a non-receptive state, causing implantation failure. Our findings define a lactic acid-HIF1α-HO-1-heme metabolic checkpoint that couples glycolytic signaling to heme regulation and endometrial receptivity. Dysregulation of this checkpoint may contribute to implantation disorders associated with heme stress, providing mechanistic insights into heme stress-related uterine receptivity failure. Full article

Articular cartilage exists under hypoxic conditions, where hypoxia-inducible factor (HIF)-1α plays a critical role in maintaining its homeostasis. In osteoarthritis (OA), however, this hypoxic environment is disrupted, and decreased HIF-1α expression contributes to disease progression. HIF-prolyl hydroxylase (HIF-PH) inhibitors stabilize HIF-1α and are clinically used to treat renal anemia; therefore, they may also exert therapeutic effects in OA through the same mechanism. However, their effects on articular cartilage remain unclear. In this study, we investigated the effects of Roxadustat, a HIF-PH inhibitor, both in vitro using rat chondrocytes and in vivo using a monosodium iodoacetate (MIA)-induced rat OA model. Roxadustat showed no cytotoxicity and significantly increased the protein expression of HIF-1α, SRY-box transcription factor 9 (SOX9), and Aggrecan in monolayer cultures. In three-dimensional spheroid cultures, Roxadustat enhanced Safranin O staining and extracellular matrix production and significantly upregulated SOX9 and ACAN mRNA expression. Furthermore, intra-articular administration of Roxadustat in the MIA-induced OA model suppressed cartilage degeneration and significantly reduced the Modified Mankin score. These findings demonstrate that Roxadustat promotes anabolic responses in chondrocytes through stabilization of HIF-1α and suppresses cartilage degeneration in OA. Intra-articular administration of HIF-PH inhibitors may represent a novel disease-modifying therapeutic strategy for OA. Full article

Clear cell renal cell carcinoma (ccRCC) is a highly immune-evasive malignancy that exhibits limited and often transient responses to immune checkpoint inhibitors (ICIs) and remains a major challenge for emerging cellular immunotherapies, including chimeric antigen receptor (CAR)-T cells. A defining feature of ccRCC, largely driven by von Hippel–Lindau (VHL) deficiency, is persistent activation of the transforming growth factor-β1 (TGF-β1) and hypoxia-inducible factor (HIF) signaling network. Acting as a central immunometabolic regulatory axis, TGF-β1/HIF promotes angiogenesis, metabolic reprogramming, epigenetic dysregulation, and immune escape through coordinated induction of immunosuppressive mediators, including PD-L1, VEGF, and CTLA-4, resulting in impaired T-cell infiltration, functional exhaustion, and resistance to immunotherapy. Preclinical studies have demonstrated that pharmacologic-dose Seleno-L-methionine (SLM) and its active metabolite, methylseleninic acid (MSA), suppress TGF-β1 and both HIF-1α and HIF-2α, leading to downregulation of multiple downstream immunosuppressive pathways at pharmacologically achievable, non-toxic concentrations. In addition to enhancing the antitumor activity of chemotherapy and VEGF-targeted agents, accumulating evidence suggests that SLM exerts broad immunologic, metabolic, and epigenetic effects that may overcome key mechanisms of therapeutic resistance. This review synthesizes current mechanistic and translational evidence supporting the repurposing of SLM as a first-in-class pleiotropic immunomodulatory agent. Using ccRCC as a model of TGF-β1/HIF-driven immune resistance, we discuss how simultaneous targeting of this central regulatory axis may restore immune surveillance, improve T-cell fitness and trafficking, enhance responses to ICIs and CAR-T cell therapy, and provide a mechanistically rational strategy for the treatment of advanced solid tumors. Full article

Hypoxia-inducible factors (HIF-1α, HIF-2α, HIF-3α) regulate cellular adaptation to oxygen deprivation, but their region-specific roles in Alzheimer’s disease (AD) and AD with cerebral amyloid angiopathy (CAA) remain unclear. Using post-mortem human brain tissue from aging, AD, and AD + CAA groups, we measured all three HIF isoforms in hippocampal subfields (CA1, CA2, CA4, dentate gyrus) and anterior cingulate cortex (ACC) layers 3 and 5. In the AD hippocampus, two distinct patterns emerged: ischemia-resistant regions (CA4, DG) maintained HIF-2α and showed relative resilience, whereas vulnerable regions (CA1, CA2) exhibited HIF-1α upregulation, HIF-3α loss, and HIF-2α dysregulation. The ACC contrasts sharply with the hippocampus by preserving coordinated HIF-1α/HIF-3α regulation during aging and AD, with layer-specific divergence (exhaustion in layer 3 vs. resilience in layer 5) emerging only upon addition of CAA. Notably, HIF-2α in ACC neurons remains stably elevated across all conditions. Taken together, our results highlight HIF-2α as a potential contributor to regional vulnerability and raise the possibility that maintaining HIF-2α levels, in addition to or instead of modulating HIF-1α, could be worthy of further investigation in the context of AD and related vascular changes. Full article

Background: Renal Cell Carcinoma (RCC) primarily affects older adults, with incidence increasing with age. Older adults remain underrepresented in clinical trials, and treatment decisions are often extrapolated from younger populations. Age-related factors such as comorbidities, frailty, polypharmacy, and immunosenescence complicate management in the geriatric population. Methods: A narrative review of the literature was conducted, focusing on localized and metastatic RCC in older adults. The review comprehensively examined the following topics: surgical interventions, active surveillance strategies, systemic therapies (including immune checkpoint inhibitors, vascular endothelial growth factor tyrosine kinase inhibitors, and hypoxia-inducible factor-2α (HIF-2α) inhibitors), toxicity profiles, and real-world outcomes. Results: Managing RCC in older adults requires balancing efficacy with tolerability. For localized disease, surveillance and minimally invasive approaches are suitable given mortality risks. In metastatic RCC, immune checkpoint inhibitor combinations and targeted therapies have improved outcomes, though toxicity may increase in frail patients. Given the favorable safety profile of HIF-2α inhibitors, these agents may play a more substantial clinical role and offer improved therapeutic utility in this patient population. Real-world data show disparities between trial populations and practice, highlighting the need for individualized treatment. Conclusions: RCC management in geriatric patients requires a shift from age-based to frailty-informed decisions. Integrating geriatric assessment enables better patient selection and treatment tailoring. Future research should focus on geriatric-adapted trials, biomarker strategies, and de-escalation approaches to improve outcomes while reducing toxicity in this population. Full article

It has been suggested that hypoxia-inducible factor 1α (HIF1α) serves as a key regulatory factor in insect metabolism remodelling under hypoxia, in which lipid metabolism appears to play an important role. However, the underlying mechanism remains incompletely understood. In this paper, the function of HIF1α in regulating lipid metabolism under hypoxia in Callosobruchus chinensis (Coleoptera: Bruchidae), a typical stored-product insect, was investigated. Based on the amplification and cloning, the sequence of the CcHIF1α gene was analysed and found to be highly conserved throughout evolution. Then HIF1α expression in the adult C. chinensis was knocked down using RNA interference (RNAi) via feeding methods. After HIF1α knockdown, insects under hypoxic conditions exhibited higher mortality, along with decreased activities of four typical antioxidant enzymes (CAT, POD, GST, and SOD) and increased levels of two peroxide products (ROS and LPO), compared to those of the control. Moreover, comprehensive lipidomic analysis using UHPLC-QE–MS/MS revealed that lipid metabolism was reprogrammed, with significant changes in the levels of lipids such as SM, LPC, PI, SQDG, MAG, PE, ACar, and TAG. In particular, the increase in ceramide (Cer) or Cer-related lipids was observed to be associated with the production of peroxides. ELISA assays further verified the effect of HIF1α on changes in these characteristic lipids, such as the increase in PA and Cer and a decrease in TAG, PC and SM. Correspondingly, the expressions of the key genes (i.e., SPTLC₁, KDSR, SMPD₃, SGPL₁, DGAT) involved in sphingolipid metabolism changed following HIF1α knockdown. These results are consistent with the possibility that HIF1α-mediated regulation of lipid metabolism may be important for insects facing hypoxic environments, and these findings could provide an in-depth understanding of insect hypoxia adaptation, thereby potentially contributing to the development of innovative pest management strategies. Full article

Background: Hypoxia and oxidative stress are central features of cutaneous melanoma biology. Body mass index (BMI) and smoking, both of which can influence systemic hypoxia, inflammation, and oxidative stress, have shown inconsistent associations with melanoma. We investigated the association of the hypoxia-inducible factor-1 alpha gene (HIF1A) rs11549465 (1772 C>T; Pro582Ser) polymorphism, alone and in combination with overweight/obesity or smoking habits, with cutaneous melanoma susceptibility and clinicopathological characteristics. Methods: This observational case–control study included 132 Caucasian Italian patients with cutaneous melanoma and 312 healthy controls. The rs11549465 polymorphism was genotyped by genomic DNA restriction fragment analysis. Logistic regression provided age- and sex-adjusted and mutually adjusted estimates. Results: Genotype and allele frequencies did not differ between patients and controls. Within the melanoma cohort, smoking for ≥20 years remained associated with metastatic disease after adjustment for BMI ≥ 25 kg/m², age at diagnosis, and sex (aOR = 3.12, p = 0.006), whereas BMI did not (aOR = 1.23, p = 0.612). Compared with healthy controls, metastatic melanoma was independently associated with BMI ≥ 25 kg/m² (aOR = 2.26, p = 0.010) and smoking for ≥20 years (aOR = 3.85, p < 0.001). Mean pack-years were higher in melanoma patients than controls (9.4 ± 16.7 vs. 5.1 ± 12.2; p = 0.002), and ≥10 and ≥20 pack-years remained associated after age- and sex-adjustment (aOR = 2.19, p = 0.001 and aOR = 3.31, p < 0.001, respectively). Mean pack-years were higher in MetM than NMetM (13.1 ± 21.0 vs. 5.9 ± 10.0; p = 0.013), and ≥20 pack-years was associated with MetM (OR = 3.05, p = 0.017). Adjusted associations with head/neck melanoma (n = 13) were observed for CC plus BMI ≥ 30 kg/m² (aOR = 9.07, p < 0.001), ≥20 cigarette/day (aOR = 5.96, p = 0.004), ≥20 years smoking (aOR = 6.64, p = 0.003), and other smoking measures. Conclusions: To our knowledge, this is the first report on the interplay between the rs11549465 polymorphism and cutaneous melanoma. HIF1A rs11549465 was not independently associated with melanoma susceptibility. Associations involving smoking, BMI, joint genotype–lifestyle exposures, and anatomical localization had wide confidence intervals and were exploratory; small subgroups and multiple comparisons require cautious interpretation and independent validation. Full article

Background/Objectives: Alzheimer’s disease (AD), one of the most prevalent neurodegenerative disorders in the elderly, is characterized by progressive cognitive loss, amyloid-β (Aβ) plaque deposition, and neurofibrillary tangle formation. Cerebral hypoxia has been reported as a complex modulator of AD pathology, with hypoxia-inducible factor-1 (HIF-1) emerging as a central molecular marker associated with neurodegeneration. This review aims to comprehensively report the roles of HIF-1 signaling in AD pathogenesis, emphasizing its neuroprotective and neurotoxic mechanisms along with demonstrating the therapeutic potential and challenges of translating this pathway for AD therapeutics. Methods: A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, Embase, and Google Scholar databases for articles published between January 2000 and December 2025 on the context. Results: Under mild hypoxic conditions, HIF-1 activation enhances neuronal survival through upregulation of glucose transporters, glycolytic enzymes, angiogenic factors, erythropoietin, and antioxidant defense mechanisms. In contrast, chronic hypoxia modulates HIF-1 into a pathogenic marker through transcriptional activation of β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and γ-secretase, facilitating amyloidogenic APP processing, along with tau hyperphosphorylation. Moreover, HIF-1 exacerbates neuroinflammation through microglial activation and pro-inflammatory cytokine release. The cell-type-specific expression patterns of HIF-1α and the temporal dynamics of its activation regulate whether the pathway exerts neuroprotective or neurodegenerative effects. Conclusions: This review discusses the current understanding of HIF-1-mediated mechanistic insights in AD pathology and impacts of existing HIF-1 modulators on AD pathology, along with the therapeutic implications of targeting this pathway for translational application in AD therapeutics. Full article

Background/Objectives: Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods: Using a murine glioma model (KR158B-luc), mice were treated with ACT consisting of tumor RNA-pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knock-out. Results: ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of recurrence under ACT. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling and enhanced DC tolerance. Conclusions: DC dysfunction is one of the key mechanisms of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia–DC axis as a promising therapeutic target to enhance immunotherapy efficacy. Full article

Feline mammary tumors are the third most common neoplasms in female cats and they are characterized by high aggressiveness and high metastatic rates. Given the pivotal role of iron in human breast cancer development, in this study, we preliminarily explore the immunohistochemical expression of proteins involved in iron uptake, storage and efflux [Transferrin Receptor 1 (TfR1), Transferrin Receptor 2 (TfR2), ferritin (FTH1), and ferroportin (SLC40A1)] in non-metastatic and metastatic feline mammary carcinomas and their tributary lymph node and the possible correlation with hypoxia-inducible factor-1 (HIF-1). Our results showed an increased expression of TfR1 and TfR2 in relation to tumor progression. FTH1 immunolabeling was mainly observed in cancer cells delimiting necrotic areas and in lymph node metastasis, indicating greater iron storage possibly associated with hypoxic environments, as suggested by increased expression of HIF-1α. Also, an increase in SLC40A1 labeling in tumoral cells suggested greater iron efflux. Although preliminary, our results underline interesting differences between feline normal and tumoral mammary tissues, which could pave the way to further in vitro studies to better understand the role of iron in the progression of feline mammary tumors. Full article

Fracture healing depends on coordinated osteogenesis and restoration of the vascular microenvironment. Endothelial cells support skeletal repair through angiogenesis, tissue perfusion and angiocrine signaling that regulates osteoprogenitor recruitment and differentiation. This narrative review examines endothelial dysfunction (ED) as a potential systemic contributor to impaired fracture healing by integrating evidence from vascular biology, experimental models and clinical studies. ED is characterized by reduced nitric oxide (NO) bioavailability, oxidative stress, inflammation and impaired vascular repair. These changes may disrupt angiogenic–osteogenic coupling through altered hypoxia-inducible factor 1-alpha subunit (HIF-1α)/vascular endothelial growth factor (VEGF) signaling, endothelial Notch activity, platelet-derived growth factor (PDGF)-mediated vascular remodeling and endothelial progenitor cell (EPC) mobilization. Conditions associated with endothelial dysfunction, including diabetes, aging, chronic kidney disease (CKD), smoking, obesity and chronic inflammatory disease, are also linked to delayed union, nonunion and poorer orthopedic outcomes. Cardiovascular disease and perioperative cardiovascular instability may further impair perfusion and physiological reserve during repair. However, the available evidence is predominantly experimental or observational, and direct causal evidence in fracture patients remains limited. Prospective studies combining standardized endothelial assessments with fracture-healing outcomes are needed to clarify clinical relevance and identify potential therapeutic targets. Full article

Sensorineural hearing loss, caused by irreversible hair cell (HC) loss, remains incurable due to the inability of the mammalian cochlea to regenerate HCs spontaneously. Although the combinatorial modulation of Notch and Wnt signaling robustly reprograms cochlear supporting cells to HCs in vitro, these strategies show limited success in vivo, which suggests that the native cochlear microenvironment imposes inhibitory cues. Here, we identify hypoxia-inducible factor 1α (HIF1α) as a critical barrier to HC reprogramming in vivo. We found that HIF1α accumulates in the basilar membrane of the intact cochlea, whereas ex vivo culture rapidly eliminates this accumulation. Mimicking the in vivo hypoxic state recapitulated the reprogramming blockade, hindering supporting cells from completing the fate transition to HCs. Mechanistically, HIF1α selectively suppressed Wnt signaling, as evidenced by the reduced expression of Wnt target genes and Wnt10a. Importantly, the pharmacological inhibition of HIF1α rescued the impaired reprogramming under hypoxia. These findings demonstrate that HIF1α accumulation in the hypoxic cochlear environment antagonizes Wnt-mediated HC differentiation, providing a mechanistic explanation for the failure of in vivo regeneration. Targeting HIF1α to restore supporting cell reprogramming competence within the hypoxic cochlear niche represents a promising, clinically translatable strategy for functional HC regeneration and hearing restoration. Full article

Cancer progression is driven by early dysregulation of the immune system and tumor-intrinsic mechanisms. Hypoxia, lactate accumulation and IL-6 signaling induce highly overlapping tumor-promoting effects, including angiogenesis, epithelial–mesenchymal transition, metastasis, immune evasion and treatment resistance, suggesting that these pathways interact and amplify one another. This parallel activation complicates therapeutic targeting, as inhibition of one pathway may be compensated for by another. Increased proteolytic activity emerges early during tumor development and profoundly alters immune regulation. We recently identified a protease-generated albumin fragment, the IL-6-inducing factor (IL-6IF), which triggers pathological IL-6 production. IL-6 in turn enhances both HIF-1α expression and nuclear translocation, promotes glycolysis and lactate production, and forms positive feedback loops with STAT3 and multiple signaling pathways. Together, these mechanisms integrate into a self-sustaining IL-6/HIF-1α/STAT3 axis that drives tumor progression and suppresses anti-tumor immunity. The strong overlap among IL-6, its enhancing loops and hypoxia-driven mechanisms highlights IL-6 as a central regulator of metabolic and immunological reprogramming in cancer. However, a broad IL-6 blockade can impair physiological immune function. Selective inhibition of IL-6IF offers a novel strategy to prevent pathological IL-6 production while preserving physiological IL-6-dependent immune function required for effective tumor control. Reducing pathologically enhanced IL-6 synthesis by targeting IL-6IF, therefore, might represent a potential therapeutic approach to disrupt multiple tumor-promoting pathways simultaneously and may thereby improve responsiveness to cancer immunotherapy. Full article

Stem cell-derived extracellular vesicles (EVs) hold therapeutic potential for hypoxia-associated injury, yet the molecular mechanisms underlying their protective effects remain incompletely defined. Herein, we performed comparative proteomic profiling of extracellular vesicles (EVs) secreted by human placenta-derived perivascular stem cells (hPPSCs) and human umbilical cord mesenchymal stem cells (hUCMSCs). We found that hPPSCs-EVs are enriched in proteasome-related proteins. Enzymatic activity assays further confirmed that proteasome activity in hPPSCs-EVs was significantly higher than that in hUCMSCs-EVs. Additionally, we observed that hPPSCs-EVs were efficiently endocytosed by human umbilical vein endothelial cells (hUVECs), leading to marked downregulation of hypoxia-inducible factor 1-alpha (HIF-1α) and intracellular ubiquitinated proteins. Importantly, this HIF-1α degradation persisted even when the host ubiquitin–proteasome system was blocked, indicating that hPPSCs-EVs can function independently of the host proteasomal pathway. These results reveal that hPPSCs-EVs deliver functional proteasomes to endothelial cells, thereby compensating for impaired protein degradation and protecting cells under hypoxic stress. Collectively, our findings provide evidence for an intercellular transfer of proteolytic capacity via stem cell-derived EVs, a mechanism that preserves endothelial proteostasis and highlights the therapeutic potential of proteasome-rich EVs for hypoxia-associated diseases. Full article