Obesity is a major global health challenge driven by profound metabolic dysregulation. Hypothalamic pro-opiomelanocortin (POMC) neurons are indispensable for whole-body metabolic homeostasis, and transient receptor potential vanilloid 4 (TRPV4) channels have emerged as regulators of metabolic control. However, the cell-type-specific function of TRPV4 in POMC neurons remains poorly defined. Herein, we demonstrate a vital role of TRPV4 in regulating POMC neuronal activity. We found that hypothalamic TRPV4 was selectively upregulated in diet-induced obese mice, but remained unchanged in genetically obese mice. TRPV4 expression levels were influenced by nutritional status and exhibited co-localization with POMC. Mice lacking TRPV4 specifically in POMC neurons showed no alterations in systemic energy metabolism under chow diet conditions. However, under high-fat diet feeding, these mice exhibited exacerbated obesity and hyperphagia. In vitro assays revealed that TRPV4 activation impaired POMC neurons by promoting mitophagy. In contrast, TRPV4 inhibition restored POMC neuronal function. Mechanistically, TRPV4 compromised POMC neuronal activity by triggering Ca2+-dependent PGAM5 activation and enhancing PINK1/PARKIN-mediated mitophagy. These findings provide comprehensive insights into TRPV4 as a critical regulator of hypothalamic energy balance circuits and highlight its potential as a therapeutic target for metabolic disorders.

Radiation-induced intestinal injury (RIII) is a serious complication of abdominal and pelvic radiotherapy. Its mechanism is complex, and traditional treatment methods are difficult to achieve precise intervention and efficacy visualization. Bardoxolone methyl (CDDO-Me) has a therapeutic effect on intestinal injury as an Nrf2 activator. However, there are limitations such as uncontrolled drug release and lack of efficacy visualization. To address this problem, we prepared a sodium alginate/hyaluronic acid (AL/HA) pH-responsive oral hydrogel loaded with CDDO-Me, and introduced melanin nanoparticles (SMNP) with enhanced MRI signal to achieve non-invasive visualization of the distribution, localization and retention of the hydrogel in rats. The hydrogel exhibited resistance to gastric acid, mucoadhesive properties, and prolonged retention in the small intestine and colon, thus achieving controlled intestinal release of drugs. In addition, our research suggested that the oral CDDO-Me@AL/HA@SMNP hydrogel could alleviate intestinal oxidative stress injury and down-regulate pro-inflammatory cytokines in mouse models. These effects may be associated with Nrf2 activation and ROS clearance, and may also involve the PI3K/Akt/GSK3β pathway. Overall, our research indicated that the CDDO-Me@AL/HA@SMNP hydrogel integrates therapeutic efficacy with MRI-based visualization/tracking capabilities for RIII. These findings represent a preclinical proof-of-concept, and further optimization, safety evaluation, and translational studies are required before any potential clinical application.

Abdominal aortic aneurysm (AAA) is a chronic vascular disorder characterized by progressive aortic wall dilation, extracellular matrix degradation, and an increased risk of catastrophic rupture. Currently, no effective pharmacological therapy is available to prevent or slow AAA progression. Neutrophil extracellular traps (NETs) have emerged as a critical pathological platform linking dysregulated innate immunity to vascular structural deterioration. In the AAA microenvironment, local inflammation, oxidative stress, metabolic disturbances, altered mechanical forces, and platelet activation collectively contribute to the induction of NETosis. Persistent NET formation promotes immunoinflammatory remodeling of the aortic wall by activating inflammatory sensing pathways, including TLR9, cGAS-STING, and NLRP3, modulating macrophage responses, inducing vascular smooth muscle cell ferroptosis and phenotypic switching, and exacerbating proteolytic degradation, oxidative injury, and immunothrombotic responses. During disease progression, NETs may transition from early drivers of inflammatory amplification to sustained regulators of vascular remodeling, while in advanced AAA they may synergize with intraluminal thrombus formation and structural destabilization to accelerate disease progression. Circulating NET-associated biomarkers represent promising candidates for complementing conventional imaging-based risk assessment; however, their specificity and predictive value require further validation. Therapeutic strategies targeting PAD4-mediated NET formation, the oxidative metabolic environment, NET-associated effector molecules, DNase I-mediated NET degradation, and nucleic acid sensing pathways have demonstrated potential in preclinical studies. This review systematically summarizes the emerging roles of NETs in AAA pathogenesis and discusses future precision strategies integrating biomarkers, multi-omics profiling, and imaging-based risk stratification with stage-specific therapeutic interventions.

Chronic wounds are a major health burden, affecting approximately 0.22% of the global population. Diabetic foot ulcers are particularly common and serious, due to their high risks of infection, amputation, and recurrence. Deferoxamine (DFO), an iron chelator that stabilizes hypoxia-inducible factor signaling and promotes angiogenesis, has been studied as a topical therapy to improve diabetic wound repair in preclinical studies. This systematic review and meta-analysis evaluates topical DFO in diabetic rat and mouse wound models. Following PRISMA guidelines and prospective PROSPERO registration, MEDLINE (PubMed), Embase, and Web of Science were systematically searched in November 2025. Internal validity was evaluated using the SYRCLE risk-of-bias tool. The primary endpoint was wound closure rate (%), and the secondary endpoint was neovascularization assessed by immunohistochemical quantification of CD31-positive vessels. Thirty-eight studies were included in the systematic review, and 29 provided sufficient data for meta-analysis. Topical DFO significantly improved wound closure (MD 13.26%, 95% CI 10.70-15.83) and increased neovascularization (SMD 2.39, 95% CI 1.64-3.14) compared to DFO-free controls (both p < 0.0001). Benefits were observed across diverse experimental settings and delivery systems. Subgroup findings further suggest that sustained local DFO availability may enhance efficacy. Topical DFO therapy demonstrates robust preclinical evidence for improving diabetic wound healing, supporting clinical translation. Future work should prioritize developing delivery platforms that enable controlled, prolonged local DFO exposure to maximize therapeutic benefit for patients with chronic wounds, especially those with diabetes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ∼30% of the global population and is associated with increased risks of heart failure (particularly heart failure with preserved ejection fraction), atrial fibrillation, and cardiovascular mortality. Despite well-established epidemiological links between MASLD and cardiovascular disease, the molecular pathways driving MASLD-related cardiac remodeling remain incompletely understood. This state-of-the-art mini review examines ferroptosis and pyroptosis as potentially convergent regulated cell-death pathways relevant to both the steatotic liver and the remodeling heart. Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death that mediates hepatocyte injury in experimental MASLD and contributes to cardiomyocyte injury under cardiac stress. Pyroptosis is an inflammasome-mediated pro-inflammatory cell death executed by gasdermin D, which amplifies tissue inflammation in hepatic and cardiac disease. Direct preclinical evidence from a pressure-overload heart-failure model demonstrates ferroptosis-to-pyroptosis signaling through the ACSL4/ALOX12/12-HETE/NLRP3 axis; however, this cascade has not yet been directly validated in MASLD models or in patients with MASLD-associated cardiac remodeling. We therefore distinguish experimentally established within-organ mechanisms from hypothesized interorgan liver-heart links, highlight shared regulators including reactive oxygen species, the cGAS/STING pathway, and the NRF2 hub, and discuss translational strategies and evidence gaps that should guide future validation.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but can disrupt ocular immune privilege and produce heterogeneous immune-related adverse events (Eye-irAEs). This structured narrative review with evidence mapping integrates clinical, epidemiologic, mechanistic, pharmacovigilance, and management data to define translational pathways from checkpoint blockade to ocular toxicity and treatment decisions. In a real-world cohort of 41,020 ICI-treated patients, ophthalmic irAEs occurred in 4.18% within 1 year, including dry eye disease in 2.00%, conjunctivitis in 0.87%, blepharitis in 0.51%, anterior uveitis in 0.39%, and keratitis in 0.38%. A 2026 meta-analysis of five cohorts comprising 277,790 participants found increased uveitis risk with ICI exposure (hazard ratio 2.26), while pooled overall survival was not significantly associated with ICI-related uveitis (hazard ratio 0.69, 95% CI 0.35-1.39). Among patients with preexisting uveitis, recurrence reached 38.9% for prior anterior disease and 51.1% for prior intermediate, posterior, or panuveitis. Risk varies by malignancy and regimen; melanoma was associated with substantially greater noninfectious uveitis than lung cancer (1.10% vs 0.18%; risk ratio 6.17, 95% CI 4.20-9.08). Mechanistically, PD-1/PD-L1 and CTLA-4 have the strongest established exposure-toxicity evidence, LAG-3 signals are emerging, and TIM-3 and TIGIT remain translational. Phenotype-directed local or systemic therapy can preserve vision and permit ICI continuation or rechallenge in selected patients. In a 2026 rechallenge series, four of five rechallenged patients had no documented recurrence, while one recurrence resolved successfully with corticosteroid treatment. Standardized phenotyping, longitudinal ophthalmic surveillance, multidisciplinary attribution, and prospective ocular endpoints should translate mechanistic insight into safer immunotherapy, individualized rechallenge, and improved cancer-treatment continuity.

Tuberculosis remains a major risk for people living with HIV, even those on antiretroviral therapy, due to increased susceptibility to latent TB infection. Identifying immune signatures that distinguish progression from resistance is critical for developing predictive biomarkers and targeted prevention strategies. In this study, 80 HIV-infected adults on antiretroviral therapy who received isoniazid preventive therapy (IPT) were followed for six months and categorized as Progressors, Sustainers, Converters, or Resisters based on serial QuantiFERON-TB results. Plasma levels of cytokines, chemokines, and growth factors were analyzed using a Luminex assay, alongside machine learning and pathway analyses. Progressors and Sustainers exhibited elevated proinflammatory cytokines, chemokines, and growth factors, while Resisters showed dynamic immune modulation following preventive therapy. Key predictors of progression included PD-L1, TNF-α, IL-17A, and FGF2. Network and pathway analyses highlighted persistent inflammatory signaling in Progressors and adaptive immune regulation in Resisters. Findings suggest distinct immune profiles associated with TB risk, offering potential for improved prediction and targeted interventions.

Nanomedicine represents one of the pivotal technologies that further bridges critical gaps in precision theranostics through targeted delivery, integrated diagnostics and therapeutics, and personalized treatment. Among various nanocarriers, extracellular vesicles (EVs) have attracted substantial interest owing to their nanoscale dimensions, favorable biocompatibility relative to synthetic counterparts, and innate capacity to transport bioactive cargoes. The central focus in this field is the inherent heterogeneity of EVs, which provides promising opportunities for biomarker-driven patient stratification while presents significant challenges in quality control and batch reproducibility. Recent progress in surface engineering has significantly optimized the targeting capability and pharmacokinetic profiles of EV-based systems in preclinical models, yet their clinical translation remains restricted by major challenges, including manufacturing scalability and the lack of disease and subgroup-specific standardization. Given that EV functionality and safety are highly context-dependent varying with cell source, loading strategy, and recipient pathophysiology bridging the gap between large-scale production and patient-specific customization emerges as a critical priority for translating EV-based nanomedicines into routine precision oncology treatment and beyond.

The nuclear receptor NOR-1 is a key transcription factor in vascular smooth muscle cells (VSMCs) implicated in the pathogenesis abdominal aortic aneurysm (AAA), a life-threatening disease lacking pharmacological options. Here, we aimed at identifying potential therapeutic targets regulated by NOR-1 in the onset and progression of AAA. RNA-seq analysis in dilated arteries from AngII-infused transgenic mice overexpressing NOR-1 in VSMCs (TgNOR-1[VSMC]) revealed an early transcriptomic signature enriched in immune-inflammatory and tissue remodeling pathways. Biologically informed analysis identified a set of genes (Spp1, Il6, Tnfsf11, Grem1, Fcgr4, Adam8 and Mmp9), linking immune-inflammatory and vascular remodeling pathways, upregulated in TgNOR-1[VSMC] dilated aortas. Re-analysis of RNA-seq datasets from human AAA aortas revealed the activation of inflammation- and extracellular matrix (ECM)-related pathways, with SPP1 and IL6 as the most upregulated genes in both clusters. In human AAA, NOR-1 expression correlated with that of SPP1 and IL6, while luciferase reporter assays and site-directed mutagenesis indicated that NOR-1 increases SPP1 transcriptional activity. Consistently, gain- and loss-of-function studies showed that NOR-1 regulates SPP1 expression. Integrative co-expression and protein-protein interaction analysis in human AAA identified SPP1 as a critical element at the cross-road between ECM remodelling and vascular inflammation. Inhibition of osteopontin (OPN, encoded by Spp1) with HY-146064 attenuated AngII-induced AAA in TgNOR-1[VSMC] mice, limiting vascular remodelling, oxidative stress, and inflammation. Overall, we identify NOR-1 as an early driver of transcriptional reprogramming in AAA, establishing the NOR-1/SPP1/OPN axis as a key mediator of the cross-talk between inflammation and vascular remodelling, and a potential therapeutic target for disease intervention.

Histone post-translational modifications play a major role in gametogenesis and early embryogenesis, being closely associated with in vitro fertilization (IVF). Proper regulation of histone modifications enables chromatin compaction, transcriptional activity, parental imprint establishment and genomic reprogramming which are essential events for zygotic genome activation and lineage specification post-fertilization. Aberrant histone regulation can disrupt epigenetic integrity, leading to impaired gamete quality, defective embryonic development, imprinting errors and potential long-term offspring implications. This review provides a critical overview of the recent findings linking assisted reproduction procedures to altered histone profiles and adverse embryonic outcomes. Emerging epigenetic strategies, including epigenetic monitoring, epigenetic editing tools (CRISPR-dCas9), optimal epigenetic quality control in IVF labs and multi-omics approaches are thoroughly discussed, aiming to optimize IVF and enhance embryo health.

Endothelial dysfunction underpins the pathogenesis of sepsis-induced acute lung injury (SI-ALI), wherein neutrophil extracellular traps (NETs) serve as pivotal mediators driving excessive inflammatory responses and progressive tissue deterioration. This study aimed to elucidate the molecular mechanism by which NETs disrupt endothelial homeostasis and promote vascular dysfunction during sepsis. In vivo mice models and in vitro endothelial cell experiments consistently demonstrated that NETs markedly exacerbated endothelial barrier disruption and autophagic flux impairment. Mechanistically, NETs-derived S100A8/A9 activated the PI3K-AKT-mTOR signaling pathway via toll-like receptor 4 (TLR4), thereby triggering endothelial pro-inflammatory and pro-adhesive phenotypic transformation. S100A8/A9 also promoted reactive oxygen species (ROS) production and NET formation in neutrophils, forming a vicious cycle. Pharmacological inhibition of S100A8/A9 or TLR4 effectively restored autophagy and mitigated sepsis-associated lung injury. Collectively, these findings reveal that the S100A8/A9-TLR4-PI3K-AKT-mTOR-autophagy axis critically mediates NETs-induced endothelial dysfunction, providing promising therapeutic targets for the intervention of septic acute lung injury.

This study is the first to investigate whether modulation of the lung microbiome after traumatic brain injury (TBI) can reduce secondary brain injury and promote neurological recovery. Moderate TBI was induced in adult male Sprague-Dawley rats, which were assigned to normal, TBI, or TBI with intratracheal neomycin treatment for three days. Bronchoalveolar lavage fluid (BAL) and lung tissues were collected on day 3, and brain neuropathology, neuroinflammation, and cognition were assessed on day 7. TBI induced marked neutrophil infiltration and alveolar interstitial edema, accompanied by elevated IL-6 and NOS2 expression in BAL fluid and increased Acinetobacter abundance (LEfSe, LDA score > 3, p < 0.05). Intratracheal neomycin treatment after TBI corrected lung dysbiosis, significantly reduced Acinetobacter abundance, and suppressed IL-6, RAGE, and NLRP3 inflammasome components (NLRP3, ASC, caspase-1, and IL-1β) in lung tissues. In the brain, neomycin improved novel object recognition, reduced IL-6, IL-1β, and NLRP3 inflammasome activation, attenuated GFAP and Iba-1 activation, decreased FJB- and TUNEL-positive cells, preserved blood-brain barrier integrity, and prevented synaptic injury. Serum IL-1β levels peaked on day 3 after TBI, but this elevation was substantially attenuated in neomycin-treated rats. Furthermore, restoration of viable Acinetobacter baumannii largely reversed the neuroprotective effects of neomycin, supporting a causal role for lung Acinetobacter in secondary brain injury after TBI. These findings suggest that early intratracheal neomycin instillation following TBI mitigates lung dysbiosis and NLRP3-mediated inflammation in both lung and brain, thereby reducing secondary brain injury via the lung-brain axis, highlighting translational therapeutic potential.