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Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier.

Submerged plants ultimately suffer from shortage in cellular oxygen availability (hypoxia) as a result of impaired gas diffusion underwater. The gaseous plant hormone ethylene is rapidly entrapped in submerged plant tissues and is an established regulator of morphological and anatomical flood-adaptive responses. Multiple recent discoveries suggest that ethylene also plays a crucial role in hypoxia anticipation and metabolic acclimation during plant submergence. Ethylene was shown to accelerate and enhance the hypoxic response through enhanced stability of specific transcription factors (group VII ethylene response factors). Moreover, we suggest that ethylene could play an important role in the induction of autophagy and promote reactive oxygen species amelioration, thereby contributing to enhanced survival during flooding, hypoxia, and reoxygenation stress.

Cytochrome c oxidase (COX) is regulated through tissue-, development- or environment-controlled expression of subunit isoforms. The COX4 subunit is thought to optimize respiratory chain function according to oxygen-controlled expression of its isoforms COX4i1 and COX4i2. However, biochemical mechanisms of regulation by the two variants are only partly understood. We created an HEK293-based knock-out cellular model devoid of both isoforms (COX4i1/2 KO). Subsequent knock-in of COX4i1 or COX4i2 generated cells with exclusive expression of respective isoform. Both isoforms complemented the respiratory defect of COX4i1/2 KO. The content, composition, and incorporation of COX into supercomplexes were comparable in COX4i1- and COX4i2-expressing cells. Also, COX activity, cytochrome c affinity, and respiratory rates were undistinguishable in cells expressing either isoform. Analysis of energy metabolism and the redox state in intact cells uncovered modestly increased preference for mitochondrial ATP production, consistent with the increased NADH pool oxidation and lower ROS in COX4i2-expressing cells in normoxia. Most remarkable changes were uncovered in COX oxygen kinetics. The p50 (partial pressure of oxygen at half-maximal respiration) was increased twofold in COX4i2 versus COX4i1 cells, indicating decreased oxygen affinity of the COX4i2-containing enzyme. Our finding supports the key role of the COX4i2-containing enzyme in hypoxia-sensing pathways of energy metabolism.

The major consequence of hypoxia is a dramatic reduction in energy production. At the onset of hypoxia, both oxygen and ATP availability decrease. Oxygen and energy sensing therefore converge to induce an adaptive response at both the transcriptional and translational levels. Oxygen sensing results in stabilization of the transcription factors that activate hypoxia-response genes, including enzymes required for efficient sugar metabolism, allowing plants to produce enough energy to ensure survival. The translation of the resulting mRNAs is mediated by SnRK1, acting as an energy sensor. However, as soon as the sugar availability decreases, a homeostatic mechanism, detecting sugar starvation, dampens the hypoxia-dependent transcription to reduce energy consumption and preserves carbon reserves for regrowth when oxygen availability is restored.

Sleep apnea, which is the periodic cessation of breathing during sleep, is a major health problem affecting over 10 million people in the United States and is associated with several sequelae, including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity may be a driver of sleep apnea. Because gaseous molecules are important determinants of CB activity, aberrations in their signaling could lead to sleep apnea. Here, we report that mice deficient in heme oxygenase-2 (HO-2), which generates the gaseous molecule carbon monoxide (CO), exhibit sleep apnea characterized by high apnea and hypopnea indices during rapid eye movement (REM) sleep. Similar high apnea and hypopnea indices were also noted in prehypertensive spontaneously hypertensive (SH) rats, which are known to exhibit CB hyperactivity. We identified the gaseous molecule hydrogen sulfide (H₂S) as the major effector molecule driving apneas. Genetic ablation of the H₂S-synthesizing enzyme cystathionine-γ-lyase (CSE) normalized breathing in HO-2 −/− mice. Pharmacologic inhibition of CSE with L-propargyl glycine prevented apneas in both HO-2 −/− mice and SH rats. These observations demonstrate that dysregulated CO and H₂S signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.

Cu/Zn superoxide dismutase (Sod1) is a highly conserved and abundant antioxidant enzyme that detoxifies superoxide (O₂•−) by catalyzing its conversion to dioxygen (O₂) and hydrogen peroxide (H₂O₂). Using Saccharomyces cerevisiae and mammalian cells, we discovered that a major aspect of the antioxidant function of Sod1 is to integrate O₂ availability to promote NADPH production. The mechanism involves Sod1-derived H₂O₂ oxidatively inactivating the glycolytic enzyme, GAPDH, which in turn reroutes carbohydrate flux to the oxidative phase of the pentose phosphate pathway (oxPPP) to generate NADPH. The aerobic oxidation of GAPDH is dependent on and rate-limited by Sod1. Thus, Sod1 senses O₂ via O₂•− to balance glycolytic and oxPPP flux, through control of GAPDH activity, for adaptation to life in air. Importantly, this mechanism for Sod1 antioxidant activity requires the bulk of cellular Sod1, unlike for its role in protection against O₂•− toxicity, which only requires <1% of total Sod1. Using mass spectrometry, we identified proteome-wide targets of Sod1-dependent redox signaling, including numerous metabolic enzymes. Altogether, Sod1-derived H₂O₂ is important for antioxidant defense and a master regulator of metabolism and the thiol redoxome.

Hyperbaric oxygen therapy (HBOT) refers to an intervention in which patients inhale near-100% oxygen at pressures exceeding 1 atmosphere absolute to increase plasma and tissue oxygen partial pressure. HBOT has been applied clinically across a broad range of conditions, including infections, inflammation, hypoxia-related injury, and malignancies. However, its immunological effects are often reduced to a binary notion of “immune enhancement” or “immunosuppression”. Moreover, substantial heterogeneity in treatment parameters and immune endpoints across studies has limited the development of a unified interpretive framework centered on peripheral immune tolerance (PIT). Following the PRISMA 2020 reporting framework, we standardized the presentation of the search and selection process. PubMed, Embase, Web of Science, the Cochrane Library, and Scopus were searched from database inception to November 15, 2025. Two reviewers independently performed study screening and data extraction. Ultimately, 39 relevant articles were included, and a mechanism-oriented qualitative narrative synthesis was conducted along the axes of oxygen tension, immunometabolism, and PIT. Across the included studies, in models of autoimmune and chronic inflammatory disease, HBOT was commonly associated with expansion of regulatory T cells and suppression of T helper 17–related inflammatory pathways, accompanied by a homeostatic recalibration of peripheral tolerance thresholds and improved tissue inflammatory outcomes. Under infectious and hyperinflammatory conditions, pro-inflammatory transcriptional signatures and cytokine responses were attenuated, markers of oxidative damage were reduced, while neutrophil directional bactericidal capacity was enhanced, suggesting synergy with certain antimicrobial therapies. In hypoxic tumor microenvironments, antigen presentation was improved, cytotoxic T-cell infiltration increased, and immunosuppressive myeloid components decreased, collectively indicating potential additive or synergistic benefits with immunotherapy. In summary, we propose an integrated framework in which upstream oxygen tension sensing drives intermediate immunometabolic remodeling, culminating in downstream reprogramming of immune cell lineages and functional states. This framework provides a testable theoretical basis for explaining the context-dependent immunological effects of HBOT across diseases and for guiding prospective study designs incorporating composite immune endpoints and therapeutic windows.

von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that causes a predisposition to renal clear-cell carcinoma, hemangioblastoma, pheochromocytoma, and autosomal-recessive familial polycythemia. pVHL is the substrate conferring subunit of an E3 ubiquitin ligase complex that binds to the three hypoxia-inducible factor alpha subunits (HIF1-3α) for polyubiquitylation under conditions of normoxia, targeting them for immediate degradation by the proteasome. Certain mutations in pVHL have been determined to be causative of VHL disease through the disruption of HIFα degradation. However, it remains a focus of investigation and debate whether the disruption of HIFα degradation alone is sufficient to explain the complex genotype-phenotype relationship of VHL disease or whether the other lesser or yet characterized substrates and functions of pVHL impact the development of the VHL disease stigmata; the elucidation of which would have a significant ramification to the direction of research efforts and future management and care of VHL patients and for those manifesting sporadic counterparts of VHL disease. Here, we examine the current literature including the other emergent pseudohypoxic diseases and propose that the VHL disease-phenotypic spectrum could be explained solely by the varied disruption of HIFα signaling upon the loss or mutation in pVHL.

In higher plants, molecular responses to exogenous hypoxia are driven by group VII ethylene response factors (ERF-VIIs). These transcriptional regulators accumulate in the nucleus under hypoxia to activate anaerobic genes but are destabilized in normoxic conditions through the action of oxygen-sensing plant cysteine oxidases (PCOs). The PCOs catalyze the reaction of oxygen with the conserved N-terminal cysteine of ERF-VIIs to form cysteine sulfinic acid, triggering degradation via the Cys/Arg branch of the N-degron pathway. The PCOs are therefore a vital component of the plant oxygen signaling system, connecting environmental stimulus with cellular and physiological response. Rational manipulation of PCO activity could regulate ERF-VII levels and improve flood tolerance, but requires detailed structural information. We report crystal structures of the constitutively expressed PCO4 and PCO5 from Arabidopsis thaliana to 1.24 and 1.91 Å resolution, respectively. The structures reveal that the PCOs comprise a cupin-like scaffold, which supports a central metal cofactor coordinated by three histidines. While this overall structure is consistent with other thiol dioxygenases, closer inspection of the active site indicates that other catalytic features are not conserved, suggesting that the PCOs may use divergent mechanisms to oxidize their substrates. Conservative substitution of two active site residues had dramatic effects on PCO4 function both in vitro and in vivo, through yeast and plant complementation assays. Collectively, our data identify key structural elements that are required for PCO activity and provide a platform for engineering crops with improved hypoxia tolerance.

Maintaining oxygen homeostasis is a basic cellular process for adapting to physiological oxygen variations in which the oxygen‐sensing pathway plays a critical role, especially in tumour progression. Little is known about the activity of the oxygen‐sensing pathway in keloid tissue. In this study, key features of the oxygen‐sensing pathway and its downstream effects were evaluated and compared between normal skin tissue and keloid tissue. Keloid tissue showed increased oxygen‐sensing pathway activation and a higher expression of key downstream factors such as tumour necrosis factor‐1α (TNF‐α) and vascular endothelial growth factor (VEGF). In addition, the effects of 2‐methoxyestradiol on the oxygen‐sensing pathway in both hypoxic and normoxic keloid fibroblasts were evaluated. Our results suggest that 2‐methoxyestradiol could be used to inhibit keloid fibroblast activity by inhibiting the oxygen‐sensing pathway and its downstream effectors.