Search Results (1,440)

Fine particulate matter (PM2.5) is a major air pollutant linked to lung cancer progression. In Southeast Asia, seasonal smoke-haze produces biomass-derived PM2.5, yet its acute effects on genetically diverse lung tumours remain unclear. We investigate how Chiang Mai haze-derived PM2.5 impacts oxidative stress and gene expression in three non-small-cell lung cancer (NSCLC) cell lines: A549 (KRAS-mutant), NCI-H1975 (EGFR-mutant), and NCI-H460 (KRAS/PIK3CA-mutant). Cells were exposed to PM2.5 (0–200 µg/mL) and assessed for viability (MTT), reactive oxygen species (ROS; H₂O₂, •OH) and malondialdehyde (MDA) levels, mitochondrial-associated fluorescence, and whole-transcriptome responses. Acute exposure caused dose- and time-dependent viability loss, with A549 and NCI-H1975 more sensitive than NCI-H460. ROS profiling normalized to viable cells revealed genotype-specific oxidative patterns: cumulative increases in A549, sharp reversible spikes in NCI-H1975, and modest changes in NCI-H460. MitoTracker intensity trended downward without significance, with subtle fluorescence changes and particulate uptake. RNA-seq identified robust induction of xenobiotic metabolism (CYP1A1, CYP1B1), oxidative/metabolic stress mediators (GDF15, TIPARP), and tumour-associated genes (FOSB, VGF), alongside repression of tumour suppressors (FAT1, LINC00472). Pathway enrichment analyses highlighted oxidative stress, IL-17, NF-κB, and immune checkpoint signaling. Together, biomass haze-derived PM2.5 from Northern Thailand drives genotype-dependent oxidative stress and transcriptional remodeling in NSCLC cells. Full article

Background: Amateur runners may benefit from combining respiratory muscle training (RMT) with resistance or aerobic modalities, but direct comparisons are scarce. This study compared different RMT-based combinations on pulmonary function, respiratory muscle strength, and whole-body exercise capacity. Methods: In this randomized four-arm trial, 48 amateur runners were allocated equally to stand-alone RMT, RMT plus upper-limb resistance (RMT + ULRT), RMT plus lower-limb resistance (RMT + LLRT), or RMT plus aerobic exercise (RMT + AET). All groups completed supervised sessions three times per week for six weeks. Pulmonary function (forced vital capacity [FVC], forced expiratory volume in one second [FEV₁], FEV₁/FVC), respiratory muscle strength (maximal inspiratory and expiratory pressures, MIP and MEP), and cardiopulmonary exercise test indices (peak oxygen uptake [VO₂peak], VE/VCO₂ slope) were assessed before and after training using standardized spirometry, mouth-pressure measurements, and treadmill cardiopulmonary exercise testing (CPET). Pre–post changes within groups and the overall between-group differences were evaluated using standard parametric methods. Results: All four interventions were associated with improvements in at least one respiratory or cardiopulmonary domain. FVC and FEV₁ tended to improve more in the resistance-combination groups, whereas the FEV₁/FVC ratio increased with RMT alone and when combined with resistance. MIP increased in the RMT, RMT + ULRT, and RMT + LLRT groups, and MEP increased across all groups. VO₂peak rose in every group, while the VE/VCO₂ slope improved only when RMT was combined with upper- or lower-limb resistance or aerobic exercise. Between-group differences in change scores were not statistically significant and did not clearly favor any single regimen. Conclusions: In amateur runners, six weeks of RMT-based programs are feasible and associated with domain-specific improvements in lung function, respiratory muscle strength, and exercise capacity. Because between-group differences in change scores were not statistically significant and the sample size was modest, these findings should be considered exploratory and may inform hypothesis generation regarding the use of different RMT combinations in future, larger trials. Full article

Background: Use of high-flow nasal cannula (HFNC) expanded from ICUs to internal medicine/respiratory wards during and after the COVID-19 pandemic, but safety and effectiveness in non-ICU settings remain uncertain. Methods: We performed a systematic review and meta-analysis of adults (≥18 years) initiated on HFNC in non-ICU wards. Primary outcomes were in-hospital (or 28-day) mortality and ICU transfer; where available, we compared mortality for HFNC vs. conventional oxygen therapy (COT) in do-not-intubate (DNI) cohorts. Observational studies and trials were eligible. Random-effects models synthesized proportions and risk ratios; risk of bias (ROBINS-I/RoB 2) and certainty (GRADE) were assessed. Results: Ten studies met the inclusion criteria for any-ward HFNC; subsets contributed data to pooled analyses. Across all non-ICU wards (general wards plus step-up IMCU/HDU), pooled mortality was 14.0% (95% CI 4.6–35.5; I² ≈ 92%). Pooled ICU transfer after ward/step-up HFNC start was 20.0% (95% CI 6.3–48.1; I² ≈ 97%). Restricted to internal medicine/respiratory wards, pooled mortality was 19.8% (95% CI 7.1–44.2; I² ≈ 95%) and ICU transfer 31.2% (95% CI 9.9–65.0; I² ≈ 97%). In step-up units (IMCU/HDU), ICU transfer appeared lower and less variable (22.0% [95% CI 16.5–28.8]; I² ≈ 10%), suggesting environment-dependent outcomes. In a multicenter DNI COVID-19 cohort, HFNC vs. COT showed no clear mortality difference (RR ≈ 0.90, 95% CI 0.75–1.08; adjusted OR ≈ 0.72, 95% CI 0.34–1.54). Certainty of evidence for all critical outcomes was very low due to observational design, high inconsistency, and imprecision. Conclusions: HFNC outside the ICU is feasible, but it is related to nontrivial mortality and frequent escalation—particularly on general wards—while step-up units demonstrate more reproducible trajectories. Outcomes appear strongly conditioned by care environment, staffing, monitoring, and escalation pathways. Given very low certainty and substantial heterogeneity, institutions should pair ward HFNC with protocolized reassessment and rapid response/ICU outreach, and future research should prospectively compare ward HFNC pathways against optimized COT/NIV using standardized outcomes. Full article

Background and Objectives: COVID-19 is an infection caused by the SARS-CoV-2 coronavirus that may develop several complications. Interstitial lung disease (ILD) is the major long-term complication of COVID-19 disease leading to progressive lung fibrosis and reduced respiratory function. The aim of this narrative review is to provide an updated overview of post-COVID-19 ILD by examining research publications and clinical guidelines selected from PubMed, Web of Science, and major respiratory medicine journals from 2020 to 2025. Methods: ILDs are diagnosed by medical history, physiological examination, pulmonary function tests, and chest X-ray or high-resolution computed tomography (HRCT) scan. Lung biopsy, especially cryobiopsy or video-assisted thoracoscopic (VATS) biopsy, can be performed to define histological patterns and confirm the diagnosis. Results: Post-COVID-19 ILD is a chronic condition characterized by long-term respiratory symptoms, radiological findings, and reduced lung function. Fibrotic injury is a consequence of the initial infection and could be influenced by persistent inflammation and dysregulated tissue repair. Risk factors include severe acute illness, advanced age, male sex, and smoking. Clinical course and prognosis of post-COVID-19 ILD is uncertain, as most patients experience gradual improvement or stability, whereas others develop progressive lung function decline. Treatment of post-COVID-19 ILD is not presently defined by guidelines but comprises corticosteroids, antifibrotics (including new drugs such as nerandomilast), supportive oxygen, pulmonary physiotherapy rehabilitation, smoking cessation, and vaccination. Conclusions: ILD represents a significant long-term complication of COVID-19 infection. Further investigations are required to better understand its pathophysiology and clinical management. As research progresses, more effective diagnostic and therapeutic strategies are expected to emerge. Full article

Portopulmonary hypertension (PoPH) and hepatopulmonary syndrome (HPS) present two vascular complications of portal hypertension, which make opposite extremes occur against the same pathophysiological background. In PoPH, vasoconstriction predominates, along with gradual remodeling of pulmonary arteries, while HPS develops due to pathological vasodilation and creation of intrapulmonary shunts. Even though they come about by different mechanisms, both disorders significantly affect quality of life, survival, and the possibility of liver transplant. In the early phases, in clinical practice, symptoms are mainly mild and nonspecific, and overlapping with symptoms of advanced liver disease often delays forming a diagnosis. In PoPH, elevated pressures in pulmonary arteries and increased vascular resistance are observed, while HPS exhibits arterial hypoxemia with normal or lowered pulmonary pressure. Standard diagnostic workup includes echocardiography, right-heart catheterization, and analysis of the arterial gases. In patients with severe PoPH, pronounced pulmonary hypertension can represent absolute contraindication for liver transplantation due to risk of acute right heart failure during operation. Conversely, HPS usually resolves itself after a successful transplant, which confirms that the transplant is an indication of being potentially curative. Therapeutic possibilities for both states are still limited. In PoPH, specific vasodilators and supportive measures are applied, while HPS treatment is mostly supportive, directed at maintaining oxygenation until the transplant. Future research should be focused on the development of targeted therapies that address vascular remodeling, angiogenesis, and oxidative stress, as well as on the standardization of diagnostic criteria and multicentric cooperation. This approach would facilitate earlier recognition, a precise assessment of transplantability, and a better long-term outcome for patients with portal hypertension and lung vascular complications. Key Points: Portopulmonary hypertension (PoPH) and hepatopulmonary syndrome (HPS) represent two opposite vascular complications of portal hypertension, posing distinct challenges for liver transplantation. This review summarizes their pathophysiology, diagnostic pathways, and therapeutic strategies, emphasizing the importance of hemodynamic profiling and multidisciplinary management to optimize transplant outcomes. Full article

Background/Objectives: Preterm infants are at risk of developing the chronic lung condition of bronchopulmonary dysplasia (BPD), with associated alveolar simplification and airway hyperreactivity. Inhibition of S-nitrosoglutathione (GSNO) reductase has been shown to rescue airway hyperreactivity in a murine model of BPD. Here, we investigate the effects of early treatment with N6022, a pharmacologic GSNO reductase inhibitor. Methods: Newborn C57BL/6 mice were exposed to either 21% (control) or 60% oxygen (BPD model) for 5 days after birth. Pups simultaneously received either subcutaneous saline or varying doses of N6022 for 5 days during hyperoxia exposure. Pups were then recovered in room air to 3 weeks postnatal age. H&E-stained lungs were analyzed for alveolar simplification and airway tethering. In vivo airway reactivity to inhaled methacholine was measured using a flexiVent system. In separate littermates, lungs were immediately harvested after 5 days of hyperoxia for protein quantification via automated capillary Westerns. Results: Alveolar simplification and decreased airway tethering were noted in the 60% + saline group. Pups treated with N6022 during hyperoxia displayed dose-dependent improvements in alveolar simplification and airway tethering. Similarly, hyperoxia-exposed pups had increased airway reactivity, as measured by elevated respiratory system resistance and elastance responses to methacholine. Treatment with 10 mg/kg/day N6022 during hyperoxia resulted in decreased resistance and elastance responses. TGF-β expressions were elevated in the 60% + saline group and attenuated in the 60% + N6022 groups. Conclusions: Early exposure to GSNO reductase inhibitors such as N6022 can prevent hyperoxia-induced alveolar simplification and airway hyperreactivity, with lasting effects even after cessation of treatment. Full article

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, leading to multi-system impairment. Sleep respiratory disorders (SRDs) are frequent in individuals with CF—even in those with normal or mildly impaired lung function—and may adversely affect overall health. The triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI) has markedly improved clinical outcomes in CF; however, its long-term impact on SRDs remains unclear. This study aimed to assess the effects of ETI on nocturnal cardiorespiratory parameters in individuals with CF over a two-year period. Thirty-five clinically stable patients aged ≥13 years, eligible for ETI therapy, were enrolled. Nocturnal cardiorespiratory polygraphy and spirometry were performed at baseline (T0), one year (T1), and two years (T2) after ETI initiation. After one year, significant improvements were observed in mean oxygen saturation (mSpO₂), time with SpO₂ ≤ 90% (t ≤ 90%), and respiratory rate. Spirometric indices (FEV₁, FVC, FEF) also significantly increased (p < 0.05). Correlation analysis revealed positive associations between mSpO₂ and FEV₁ (ρ = 0.515, p = 0.002) and between FEV₁ and FVC (ρ = 0.894, p < 0.001), while t ≤ 90% negatively correlated with FEV₁ (ρ = −0.404, p = 0.016). No additional significant changes were found at T2. ETI therapy resulted in sustained improvements in nocturnal oxygenation and lung function, supporting the importance of nocturnal respiratory monitoring during follow-up. Full article

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu–Osler–Weber syndrome, is a disorder of angiogenesis characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. This rare autosomal dominant disorder is caused by pathogenic variants in the ENG and ACVRL1 genes, and only 1–3% of case variants occur in SMAD4. HHT clinical manifestations include telangiectasias, epistaxis, and arteriovenous malformations in multiple organ systems. Clinical diagnosis is based on Curaçao Criteria. Here, we describe a pauci-symptomatic 10-year-old girl with an orbital and sinus infectious disease. Her clinical history was unremarkable, except for sporadic, self-limiting epistaxis episodes. She showed finger clubbing and low oxygen saturation levels on pulse oximetry, suggesting a chronic lung disease, and a large lung arteriovenous malformation. She also developed acute neurological symptoms, with evidence of multiple cerebral abscess lesions on MRI. HHT was therefore suspected and confirmed by genetic analysis, which revealed a de novo pathogenic variant in the ENG gene [c.1183G>T p.(Glu395Ter)] found in only 15% of the reads from NGS analysis, performed on peripheral blood lymphocytes, indicating a possible mutational mosaicism. This case outlines that HHT could present with unusual clinical symptoms highlighting the importance of diagnosis using both clinical criteria and genetic test. Full article

E-cigarettes (E-cigs) are increasing in popularity and are considered a potentially safer alternative to traditional cigarettes. However, prior studies have demonstrated that inhalation of nicotine-containing e-cigs can cause substantial pathophysiologic changes, and “vaping” of some substances has led to severe lung damage. Our group recently described the role of cortactin (CTTN), a cytoskeletal actin-binding regulatory protein, in mediating cigarette smoke (CS) and E-cig-induced lung endothelial apoptosis and mitochondrial dysfunction. In the current study, we advance this work by characterizing the effects of E-cig on lung endothelial nanomechanical properties and barrier function. Lung EC exposure to E-cig extract (50 µg/mL) resulted in disruption of endothelial barrier properties as assessed by Electric Cell–Substrate Impedance Sensing (ECIS). Since excess mitochondrial reactive oxygen species (mitoROS) is an important marker of mitochondrial dysfunction, we next assessed the effect of Mito-TEMPO (10 µM, 3 h), a cell-permeable antioxidant, on E-cig-induced endothelial permeability. Pretreatment with Mito-TEMPO provided EC barrier protection after E-cig challenge, suggesting a key role of mitoROS in E-cig-induced EC permeability. E-cig exposure induces cytoskeleton rearrangement, leading to gap formation in lung EC, and significantly alters EC elastic properties as assessed by atomic force microscopy (AFM). Reduction in CTTN expression by siRNA further augmented the injurious effects of E-cig on EC permeability and elastic properties. This is the first study to explore the role of CTTN in evaluating the effect of E-cigarette exposure on the lung endothelium using AFM and provides novel mitochondrial and biophysical characterization of the effects of E-cig exposure on human lung EC. This work advances our understanding of the pathophysiologic effects of E-cig exposure. Full article

Background: Early reports highlighted unique features of COVID-19-associated ARDS. The combination of prone position (PP) and positive end-expiratory pressure (PEEP)-induced lung recruitment maneuver (LRM) has demonstrated efficacy in enhancing oxygenation and improving outcomes in patients with ARDS, but it remains unknown whether there is a difference between COVID-19 ARDS and non-COVID-19 ARDS. Method: This study is a secondary analysis of a previously conducted randomized controlled trial. Patients with moderate to severe ARDS were consecutively enrolled during the study period (June–December 2023). After initiation of PP, patients received a PEEP-induced LRM followed by 12 h of daily PP. The interventions were repeated at least three times over the subsequent 3 days. Clinical outcomes, respiratory mechanics, and electrical impedance tomography (EIT) results were evaluated. Results: Twenty-eight patients were included in the final analysis, half of whom were infected with COVID-19 (50%). The PEEP-induced LRM led to greater improvement in oxygenation among COVID-19 ARDS than non-COVID-19 ARDS (∆PaO₂/FiO₂ ratio 90.5 mmHg vs. 65.5 mmHg, p < 0.05). Based on EIT measurement, compared with the non-COVID-19 ARDS group, PEEP-induced LRM resulted in a greater increase in ventilation distribution, mainly in the dorsal regions of interest 4 (ROI 4) ventilation distribution (∆ROI4 4.5% vs. 1.0%, p = 0.01) and in dorsal regional ventilation (∆dorsal regional ventilation 10.0% vs. 5.5%, p = 0.04) in the COVID-19 ARDS group. Conclusions: Compared to typical ARDS, PEEP-induced LRM combined with PP may be more effective in enhancing oxygenation in COVID-19-related ARDS. Full article

Background: Noble gases, such as argon, have been observed to exhibit cytoprotective effects. The non-anesthetic properties, abundance, and cost-effectiveness of argon suggest its clinical potential. While its efficacy in mitigating ischemia–reperfusion injury has been demonstrated in cellular and small animal models, data on its effects in large animals remain limited. This study evaluated the effects of argon inhalation on pulmonary ischemia–reperfusion injury in miniature swine with potential applications in transplantation. Methods: The left bronchial and pulmonary artery and veins were clamped for 90 min, and then the clamps were released to induce lung ischemia–reperfusion injury in 10 CLAWN miniature swine. The argon group (n = 5) inhaled a mixture of 30% oxygen and 70% argon for 360 min, whereas the control group (n = 5) inhaled a mixture of 30% oxygen and 70% nitrogen for an equivalent duration. Lung function was evaluated using chest X-ray, lung biopsies, and blood gas analysis. Results: The PaO₂/FiO₂ ratio significantly decreased in the control group 2 h post-reperfusion (568 ± 12 to 272 ± 39 mmHg), but was better preserved in the argon group (562 ± 17 to 430 ± 48 mmHg). Blood gas from the left pulmonary vein showed a superior PvO₂/FiO₂ ratio in the argon group (331 ± 40 vs. 186 ± 17 mmHg at 2 h; 519 ± 19 vs. 292 ± 33 mmHg at 2 days). Chest X-ray revealed reduced infiltration in the left lung. The lung biopsy histological scores improved in the argon group at 2 h and 2 days. Serum superoxide dismutase analysis and tissue TUNEL assays suggested that antioxidant and anti-apoptotic mechanisms, respectively, were involved. Conclusions: Perioperative argon inhalation attenuates ischemia–reperfusion injury in swine lungs, likely via anti-apoptotic and antioxidant effects. Full article

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and vascular maturation. In a postnatal high-oxygen-induced rat model of BPD-associated lung injury, three or five days of exposure to 80% oxygen was found to disrupt developmental signaling pathways, downregulating genes essential for alveolarization and angiogenesis while inducing profibrotic mediators and collagen expression (Sirius Red staining). These changes resulted in simplified alveolar architecture, as quantified by toluidine blue staining and mean linear intercept analysis of normalized volumes of parenchyma, non-parenchyma, airspaces, septa, and edema. Acting as a multifunctional antioxidant with antifibrotic activity, caffeine mitigated structural lung damage and normalized the transcription of angiogenic and fibrotic genes. It counteracted TGF-β/CTGF-driven fibrogenic signaling and promoted recovery of normal lung morphology following hyperoxic injury. Under normoxic conditions, however, caffeine transiently upregulated profibrotic mediators. Overall, caffeine mitigates hyperoxia-induced lung injury and may actively promote physiological lung maturation, warranting future studies to define optimal dosing windows, clarify context-dependent fibrotic signaling, and translate gene-level effects into long-term clinical outcomes. Full article

Introduction: Since COVID-19 primarily targets the respiratory system, it is essential to longitudinally monitor functional capacity and pulmonary function in individuals with post-COVID syndrome (PCS). This study aimed to evaluate the functional capacity of individuals with PCS during exercise using cardiopulmonary exercise testing (CPX) and examine its association with spirometry, impulse oscillometry (IOS), and lung ultrasound (LUS) parameters. Methods: Sixty individuals participated in this study. We assessed CPX, which measured peak oxygen consumption (VO₂peak), in addition to IOS, spirometry, and LUS. Results: The mean VO₂peak was 18.4 ± 5.9 mL/kg/min. Significant negative correlations were found between VO₂peak and the following parameters: age (r_s = −0.465, p = 0.0002), body mass index (BMI, r_s = −0.354, p = 0.0056), resonance frequency using IOS (r_s = −0.312, p = 0.0193), and LUS aeration score (rs = −0.261, p = 0.0439). Conclusions: Patients with PCS undergoing CPX demonstrated impaired functional capacity. In these individuals, higher age and BMI were associated with lower VO₂peak. Furthermore, alterations in LUS and IOS may also be linked to reduced VO₂peak. These findings are promising, as they were obtained using a low-cost device. Further studies are needed to investigate the factors that influence oxygen consumption in PCS. Full article

Background: Interstitial lung diseases (ILDs) profoundly affect daily life, limiting mobility, independence, and emotional stability. While antifibrotic therapies may slow physiological decline, the living experience—characterized by breathlessness, cough, frailty, and psychological distress—remains insufficiently understood; this study therefore aimed to capture real-world patient perspectives on functional capacity, self-management, and mental health to identify treatable traits beyond conventional physiological measures. Materials and Methods: A cross-sectional quantitative online survey was conducted between September 2024 and January 2025 by Lungenfibrose e.V. in collaboration with the Center for Interstitial and Rare Lung Diseases (ZISL), Universities of Giessen and Marburg Lung Center (Giessen site). Patients with physician-confirmed ILD completed standardized instruments assessing dyspnea (MRC), cough intensity (VAS-Cough), frailty (CFS), and health-related quality of life (EQ-5D-5L). Data were analyzed descriptively across physical, functional, and psychosocial domains. Results: The majority of 69 respondents had idiopathic pulmonary fibrosis (64.7%) with a mean diagnostic delay of 1.4 ± 2.2 years; 69% were diagnosed within two years of symptom onset, and 77% were receiving antifibrotic therapy (nintedanib 57%, pirfenidone 19%). Functional limitations were substantial—55% were mobile for fewer than two hours per day, 73% reported mobility impairment, and oxygen use was common (51% during exertion, 26% at rest). Frailty increased over time (mean CFS 3.2 → 3.8), with 46% classified as fit, 36% vulnerable, and 18% frail. Dyspnea and cough remained burdensome (mean VAS-cough 40 ± 26; 58% moderate–severe), and health-related quality of life was reduced (mean EQ-VAS 56.5 ± 23.7), with high rates of anxiety/depression (78%), limitations in daily activities (76%), and pain/discomfort (74%). Despite overall satisfaction with care (mean 7.1 ± 2.5), respondents frequently reported unmet needs for psychological support and clearer communication about treatment and disease management. Conclusions: Despite antifibrotic therapy and structured specialist care, individuals living with ILD continue to face substantial physical and emotional challenges. Treatable traits—including frailty, dyspnea, inactivity, anxiety, and social isolation—emerge as key determinants of well-being. Multidisciplinary strategies integrating rehabilitation, psychosocial support, and patient education alongside pharmacological therapy are essential to preserve autonomy and improve quality of life in pulmonary fibrosis. Full article

Cancer cell plasticity drives metastasis and therapy resistance through dynamic transitions between epithelial, mesenchymal, and neural crest stem-like (NCSC) states; however, a unifying mechanism that stabilizes these transitions remains undefined. To address this gap, we introduce a N-cadherin (CDH2)-centered redox–adhesion–exosome (RAX) hub that links oxidative signaling, adhesion dynamics, and exosome-mediated immune communication into a closed-loop framework. Within this network, reactive oxygen species (ROS) pulses license epithelial–mesenchymal transition (EMT), AXL–FAK/Src signaling consolidates mesenchymal adhesion, and selective exosomal cargoes—including miR-21, miR-200, miR-210, and PD-L1—propagate plasticity and immune evasion. Lipid peroxidation acts as a central checkpoint connecting ROS metabolism to PUFA membrane remodeling and ferroptosis vulnerability, buffered by NRF2–GPX4 and FSP1/DHODH axes, thereby converting transient oxidative pulses into persistent malignant states. Mechanistically, the RAX hub synthesizes findings from EMT/CSC biology, ferroptosis defenses, and exosome research into a self-reinforcing system that sustains tumor heterogeneity and stress resilience. Evidence from single-cell and spatial transcriptomics, intravital ROS imaging, and exosome cargo-selector studies supports the feasibility of this model. We further outline validation strategies employing HyPer–EMT–CDH2 tri-reporters, CRISPR perturbation of YBX1/ALIX cargo selectors, and spatial multi-omics in EMT-high tumors. Clinically, tumors enriched in EMT/NCSC programs—such as melanoma, neuroblastoma, small-cell lung cancer, pancreatic ductal adenocarcinoma, and triple-negative breast cancer (TNBC)—represent RAX-dependent contexts. These insights highlight biomarker-guided opportunities to target adhesion switches, ferroptosis defenses, and exosome biogenesis through lipid peroxidation-centered strategies using liquid-biopsy panels (exosomal CDH2, miR-200, miR-210) combined with organoid and xenograft models. By linking lipid peroxidation to ferroptosis defense and oxidative stress adaptation, the RAX hub aligns with the thematic focus of lipid metabolism and redox control in cancer progression. Collectively, the RAX framework may provide a conceptual basis for precision oncology by reframing metastasis and therapy resistance as emergent network properties. Full article