Hyperoxia-induced acute lung injury (HALI) is a serious complication of excessive oxygen exposure, yet its pathogenesis and treatment remain incompletely understood. A growing body of evidence suggests that HALI results from the interplay of oxidative stress, inflammation, immune dysregulation, organelle dysfunction, alveolar barrier disruption, and regulated cell death. In this review, we summarize recent advances in our understanding of these processes and discuss therapeutic strategies that have been investigated in experimental models. These approaches include antioxidant and anti-inflammatory agents, metabolic and mitochondrial modulators, interventions targeting iron metabolism and ferroptosis, barrier-protective therapies, and cell- or extracellular vesicle-based treatments. We also consider the limitations of the current evidence, particularly the differences between experimental models and clinical settings and the safety, delivery, and reproducibility challenges associated with emerging therapies. Further studies are needed to define the key regulatory mechanisms and temporal features of HALI, establish clinically relevant experimental models, and generate stronger clinical evidence to determine whether promising experimental interventions can be translated into effective therapies.
BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) are a cornerstone of multimodal analgesia after total knee arthroplasty (TKA), but gastrointestinal, renal, cardiovascular, and bleeding risks may limit their perioperative use in some older adults. This study evaluated preoperative photobiomodulation therapy (PBMT) delivered with a stationary 810 nm semiconductor laser as a non-pharmacological pre-emptive analgesic strategy compared with celecoxib.MethodsIn this prospective, double-blind, double-dummy randomized controlled trial, 80 patients undergoing primary unilateral TKA were randomized 1:1 to preoperative PBMT (n = 40) or oral celecoxib (n = 40). The primary outcome was resting visual analogue scale (VAS) pain at 24 h after surgery. The non-inferiority margin was 1.0 VAS point and the assumed standard deviation for sample-size calculation was 1.5 points. Other pain time points, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), lower-limb swelling, early joint function, perioperative blood loss, and complications were also assessed.ResultsAt 24 h, resting VAS pain was 3.9 ± 1.1 with PBMT and 3.7 ± 1.0 with celecoxib (PBMT minus celecoxib mean difference, 0.20 points; 95% CI, −0.27–0.67); the upper confidence limit was below the 1.0-point margin. The 48-h WOMAC scores were 42.4 ± 5.8 and 41.8 ± 6.2, respectively (P = 0.655). PBMT was associated with smaller increases in thigh circumference on postoperative days 3 and 7, less hidden blood loss, and fewer reports of gastrointestinal discomfort.ConclusionPreoperative 810 nm semiconductor-laser PBMT met the stated non-inferiority criterion for 24-h resting pain compared with celecoxib and was associated with favorable swelling, blood-loss, and gastrointestinal outcomes.
The Wound Healing Assay is a standard technique for studying cell motility, yet it faces challenges in reproducibility and data interpretation. Here we present WoundPy, a Python-based executable software featuring a user-friendly interface for semi-automatic, researcher-supervised Region of Interest detection. WoundPy streamlines image analysis and management of replicates, providing rapid graphical outputs. A key pre-processing feature is the automated vertical wound alignment, which eliminates operator-dependent errors typical of optical microscopy. Velocity results are calculated as absolute values from multi-time-point imaging. The software was tested on three datasets from biological experiments, and a comparison with ImageJ Wound Healing Size tool revealed a significant underestimation of the wound area by the latter compared to WoundPy. In conclusion, this new software offers an extremely streamlined approach that easily enables to perform an analysis that is both accurate and fast, drastically reducing the time required for both numerical data acquisition and its subsequent analysis.
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease with limited therapeutic options and a median survival of only 3–5 years. Although antifibrotic agents such as pirfenidone (PFD) and nintedanib can decelerate functional decline, they fail to reverse established fibrosis, underscoring an urgent need for novel therapeutic paradigms. Emerging evidence has positioned mitophagy—the selective autophagic clearance of damaged mitochondria—at the nexus of IPF pathogenesis. In this review, we systematically dissect the regulatory networks governing mitophagy, encompassing the canonical PINK1/Parkin pathway, receptor-mediated mechanisms (BNIP3/NIX/FUNDC1), and their intricate cross-talk with endoplasmic reticulum stress (ERS) and ferroptosis, highlighting how these interconnected pathways converge to determine alveolar epithelial cell (AEC) fate, fibroblast activation, and inflammatory reprogramming. Notably, the pathological impact of mitophagy is highly cell-type-specific and context-dependent, exhibiting protective functions in epithelial cells while paradoxically promoting pro-fibrotic phenotypes in macrophages under certain conditions, which poses both challenges and opportunities for therapeutic intervention. Furthermore, we critically evaluate emerging pharmacological and biological strategies targeting mitophagy, and propose that future combination regimens—guided by non-invasive mitophagy biomarkers—may overcome current clinical bottlenecks. By integrating mechanistic insights with translational perspectives, this review provides a roadmap for developing mitophagy-targeted interventions as a next-generation therapeutic paradigm for IPF.
Regulatory T cells (Tregs) maintain immune homeostasis, but in cancer the same FOXP3-dependent programme can be co-opted to protect malignant tissue from immune elimination. This review critically synthesizes spatially resolved, single-cell and mechanistic evidence to determine when tumour-associated Tregs constitute active components of suppressive multicellular niches rather than merely correlates of immune exclusion. We integrate tumour-adapted regulatory states with anatomical positioning, neighbouring malignant and non-malignant cells, candidate suppressive mechanisms and upstream tumour-intrinsic, stromal and myeloid programmes. This framework distinguishes Treg-dominant suppressive niches from Treg-associated architectures in which regulatory-cell accumulation is secondary to other resistance mechanisms. We examine tumour nests, invasive margins, dendritic-cell and lymphoid aggregates, stromal and perivascular barriers, and hypoxic or metabolically constrained regions, assessing the strength of evidence linking each context to local immune restraint. We further consider how these niches emerge during tumour progression, change under therapeutic pressure, and persist, relocate or re-form during resistance. We evaluate selective depletion strategies targeting CCR8, CD25 and CTLA-4, together with functional reprogramming of TGF-β, adenosine, kynurenine, lactate, hypoxia and IL-2 pathways. Finally, we propose a tiered biomarker framework integrating Treg phenotype, transcriptional state, spatiotemporal topology, functional immune competence and longitudinal pharmacodynamic validation. The contribution of this Review is therefore not the niche concept itself, but its Treg-centred mechanistic and translational operationalization for identifying tumour-specific regulatory dependencies while preserving systemic self-tolerance.
Lipid droplets and mitochondria form regulated contact sites whose molecular composition, phosphorylation state and spatial geometry now behave as measurable, druggable variables in living cells. The molecular toolkit has been mapped in liver, muscle and adipose tissue, yet its application to respiratory disease has lagged despite a lung-specific dependence on lipid biology that spans surfactant biogenesis, alveolar-macrophage lipid handling and fibroblast-driven remodelling. This review argues that the lipid-droplet–mitochondria contact site is an emerging spatial-pharmacology target in respiratory medicine, and organises the evidence into a three-way matrix with explicit grading of direct, indirect and cross-tissue evidence. A common molecular toolkit built around perilipin-family scaffolds, mitochondrial-outer-membrane tethers, an endoplasmic-reticulum bridging apparatus and the PFKL–PLIN2–CPT1A flux node (mechanistically established in hepatocellular carcinoma and inferred in lung) is rewired into cell-type-specific configurations across alveolar type 2 cells, macrophages, fibroblasts, endothelium and lung adenocarcinoma. That toolkit acquires a distinct disease role across idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, tuberculosis, severe acute respiratory syndrome coronavirus two infection and lung cancer, generating a matrix of cell-type-by-disease configurations that no prior review has systematized. Four target axes, namely, tether occupancy, lipid flux, redox coupling and cell-type-precise delivery, converge geometrically at the interface and motivate combination strategies rather than pan-mitochondrial single-agent approaches. Inhaled lipid nanoparticles, mucus-penetrating carriers and engineered extracellular vesicles bring these targets within reach with cell-type precision. Endothelial contact-site biology is identified as the largest evidence gap and discussed candidly. The framework is offered as a roadmap for tether-axis compound development, contact-site engagement biomarkers and dual-axis inhaled therapeutics.
Diabetic foot ulcer (DFU) is a severe and difficult-to-heal complication of diabetes in which systemic metabolic dysregulation is translated into local neurovascular injury and dysfunction of wound-healing cells. This narrative review examines the relationships among glucose, lipid, and amino acid/protein metabolism disorders, the dysfunction of macrophages, fibroblasts, and endothelial cells, and hydrogel-based therapeutic strategies. Persistent hyperglycemia disrupts the tricarboxylic acid cycle, activates the polyol and advanced glycation pathways, and induces pseudohypoxia, oxidative stress, and inflammatory metabolic reprogramming. Dyslipidemia promotes lipid peroxidation, mitochondrial injury, impaired fatty acid oxidation, and ferroptosis, whereas amino acid and protein metabolic abnormalities disturb insulin signaling, arginine metabolism, collagen-precursor availability, and extracellular matrix turnover. These metabolic alterations sustain pro-inflammatory macrophage programs, impair fibroblast migration and matrix production, and compromise endothelial angiogenesis. We further critically compare hydrogel systems that provide glucose-responsive insulin release, catalytic glucose consumption and oxygen generation, lipid-peroxide scavenging, immunometabolic regulation, and support for extracellular matrix remodeling and vascular regeneration. Metabolism-targeted hydrogels provide a promising bridge between mechanistic metabolic intervention and local wound management; however, most available evidence remains preclinical. Future translation requires direct validation of metabolic regulation, standardized manufacturing, long-term biosafety assessment, and evaluation in clinically relevant DFU models.
Small nucleolar RNAs (snoRNAs) are best known as guide RNAs for ribosomal RNA modification, but accumulating evidence indicates that their biology extends beyond canonical ribosome maturation. Across GBM-specific and broader glioma studies, snoRNAs, snoRNA-derived RNAs (sdRNAs), and associated small nucleolar ribonucleoprotein components are emerging as regulators of malignant cell states. This review frames GBM-associated snoRNA and sdRNA alterations as a cell-biological remodeling process that links ribosome biogenesis, metabolic adaptation, treatment response, and extracellular-vesicle output. Across currently available GBM and broader glioma studies, tumor-restraining C/D-box snoRNAs, including SNORD76, SNORD47, SNORD44, and SNORD113-3, tend to be reduced, and restoration of several of these molecules suppresses malignant phenotypes in their respective experimental systems. Conversely, tumor-supporting snoRNA-associated activities, including the U3–PHAX–DNA-PKcs–TRIM24 complex, a U3-derived small RNA acting through ZBTB7A, and preprint-based H/ACA snoRNA/snoRNP activity involving dyskerin, are maintained, increased, or functionally co-opted in specific GBM-related contexts. These alterations converge on three recurrent cellular contexts: translational capacity, glucose and glycolipid metabolism, and survival under radiotherapy or temozolomide. Treatment-associated senescence may also reshape extracellular-vesicle snoRNA cargo, with SNORA49 detected in a small longitudinal plasma series, although this remains exploratory rather than a validated liquid-biopsy marker. We also emphasize the need to distinguish snoRNAs and sdRNAs from their SNHG host transcripts, because these molecular entities have distinct biogenesis and mechanisms. Together, these studies suggest a context-dependent pattern of snoRNA and sdRNA dysregulation across GBM and related glioma models, with the strength of evidence varying among individual molecular axes. SnoRNAs and sdRNAs should be viewed as an emerging regulatory layer in GBM rather than as established therapeutic targets. Future work should validate molecule-specific snoRNA and sdRNA axes in disease-relevant models and determine whether extracellular-vesicle snoRNAs provide reproducible readouts of treatment-associated cell states.
Oncofetal antigens are emerging targets for chimeric antigen receptor (CAR)-based immunotherapies due to their developmentally restricted expression and frequent re-emergence in malignant cells. These antigens are tightly linked to cellular plasticity, stem-like programs, immune evasion, and resistance to cytotoxic therapies, making them biologically compelling targets. Multiple oncofetal antigens have entered early-phase clinical trials as CAR-T cell targets with promising results in several cancers including neuroblastoma and diffuse midline gliomas. However, antitumor efficacy in most solid malignancies has thus far been modest. This reflects shared obstacles, including low-level expression in normal tissues, intratumoral antigen heterogeneity, immune suppression within the tumor microenvironment, CAR-T cell exhaustion, and limited persistence. In this Mini-Review, we discuss the biological foundations of oncofetal antigen expression, synthesize clinical and pre-clinical experience targeting these antigens with CAR-T cell therapies, and highlight emerging engineering and combination strategies designed to overcome current limitations. We propose that integrating principles from developmental biology, tumor evolution, and immuno-engineering will be essential to unlocking the therapeutic potential of oncofetal antigen-directed CAR-T therapies in solid tumors.
BackgroundPitt-Hopkins Syndrome (PTHS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the TCF4 gene. It is characterized by intellectual disability, distinctive facial features, breathing abnormalities, and gastrointestinal dysfunction. While the role of TCF4 in central nervous system development has been extensively investigated, the developmental basis underlying craniofacial and enteric alterations remains poorly understood.MethodsWe generated a zebrafish tcf4 mutant line using CRISPR/Cas9 genome editing to unveil the role of Tcf4 in neural crest-derived lineages that contribute to craniofacial and Enteric Nervous System development. The model was characterized by multiple integrated approaches to evaluate the morphological, cellular and functional alterations associated with tcf4 haploinsufficiency. As a proof-of-concept that the observed phenotypes resulted from Tcf4 loss of function, we reinstated human TCF4 expression in mutant larvae and assessed the rescue of the pathological phenotypes previously described.ResultsHeterozygous mutants exhibit key features of PTHS, including craniofacial skeletal abnormalities and impaired gastrointestinal motility. Functional analysis revealed a significant reduction of spontaneous peristaltic contractions and a delayed swallow-induced gut transit, consistently with human patients and PTHS mouse model. To further elucidate these developmental alterations, we showed that these defects are associated with a reduced number of Phox2b-positive enteric progenitors and HuC-positive enteric neurons, though early vagal neural crest migration appears unaffected. Reintroducing human TCF4 mRNA in tcf4 heterozygous mutant embryos rescues both craniofacial and gastrointestinal phenotypes, confirming the specificity of the observed phenotypes. Furthermore, we showed that the human TCF4 mRNA overexpression can alter craniofacial development in zebrafish embryos suggesting that TCF4 reinstatement dosage should be evaluated in gene therapy approaches to avoid a gain of function phenotype.ConclusionTogether, our results shed light on TCF4 as a key regulator of neural crest-derived lineages and provide a new perspective on two major clinical features of PTHS. The tcf4 mutant line represents a novel in vivo platform for investigating PTHS pathogenesis at cellular and molecular level and testing novel therapeutic strategies
Sound detection occurs in the cochlea, where sensory inner hair cells (IHC) accurately convert auditory stimuli into neurochemical signals. Presynaptically, IHCs harbor synaptic ribbons, specialized scaffolds that facilitate ultrafast and indefatigable exocytosis. During synapse assembly and subsequent maturation, IHC ribbons increase in volume and synaptic vesicle tethering capacity. This development is thought to result from progressive precursor aggregation. However, the underlying mechanisms of ribbon synapse formation have remained elusive thus far. In this study, we established a novel triple-color live-cell imaging approach to monitor IHC presynaptogenesis in situ. We found that ribbon precursors are highly dynamic and undergo bidirectional plasticity. The presynaptic active zone (AZ) forms a focal point for dramatic structural remodeling of precursors, which the AZ recruits, confines and redistributes. Furthermore, silencing spontaneous synaptic activity decreased precursor mobility and plasticity at the AZ. This suggests a fundamental role for activity-dependent Ca2+ influx in regulating the dynamic assembly of auditory ribbon synapses.
Mitochondria play a central role in cells through energy production, calcium regulation, and cell death regulation. Dysfunction of mitochondria can impair energy production causing cellular damage which could be detrimental to an organism. Mitochondrial dynamics such as fission, fusion, and motility determine the organelle’s structure and can indicate the overall health of the cell. Dictyostelium discoideum, a well-established model for mitochondrial dynamics, contains two GTPase proteins that are predicted to mediate mitochondrial dynamics, FszA and FszB. In this study, we overexpressed GFP tagged FszA and FszB proteins to gain insight into their role in the mitochondrial dynamics of D. discoideum. Through live imaging, we quantified mitochondrial fission and fusion events, localization of the proteins with respect to fission and fusion events, and mitochondrial velocity. Results show that the overexpression of FszA-GFP, FszB-GFP, and GFP-FszB significantly decreased mitochondrial fission and fusion, and overexpressed GFP-FszA significantly decreased mitochondrial fusion compared to the control AX4 strain. Images of GFP-FszA and FszA-GFP strains showed little co-localization with the mitochondria during fission and fusion events, but GFP-FszB and FszB-GFP were localized to the mitochondria during fission events. Overexpression of FszB-GFP and GFP-FszB also significantly decreased mitochondrial velocity. The results of this study give insight into the underlying mechanism behind mitochondrial dynamics and could advance future studies in D. discoideum neurodegeneration models.
The dynamic evolution of fundus tessellation density (FTD) and peripapillary atrophy (PPA) during childhood myopia progression—and their threshold-associated transitions relative to axial length (AL)—remain incompletely characterized. To address this gap, we prospectively quantified longitudinal FTD and PPA changes in a school-aged cohort with progressive myopia, and modeled their nonlinear dose–response relationships with AL to identify the biomechanical threshold at which fundus remodeling shifts from physiological adaptation to early pathological tissue deformation. A cohort of 371 children aged 8–11 years was prospectively followed for 2 years. FTD and PPA were measured via a validated deep learning system; myopia progression subtypes were stratified via k-means clustering by annual AL elongation rate; longitudinal trajectories and inflection points were estimated via linear mixed-effects models and quadratic regression. Three progression phenotypes emerged: stable (0.147 mm/y), moderate (0.443 mm/y), and rapid (0.827 mm/y). Each 1 mm AL increase correlated with 0.127 mm2 (95% CI 0.106–0.148) PPA expansion (p < 0.001) and 0.011 FTD elevation (p < 0.001). PPA showed J-shaped acceleration with inflection at 23.99 mm; FTD showed U-shaped trajectory, declining before 23.66 mm then rising exponentially. This is the first longitudinal study to identify a ∼24 mm (23.66–23.99 mm) biomechanical threshold for early fundus pathology in children—substantially below the adult high-myopia criterion (>26 mm)—supporting a paradigm shift toward earlier AL-driven risk stratification based on tissue biomechanical susceptibility rather than conventional static refractive cutoffs.
Degenerative skeletal diseases, including osteoarthritis (OA), intervertebral disc degeneration (IVDD) and osteoporosis (OP), are major causes of chronic pain, disability and loss of skeletal function, yet effective disease-modifying therapies remain limited. Although these disorders affect distinct tissues and cell populations, they share persistent inflammation, oxidative stress, mitochondrial dysfunction, metabolic imbalance and defective tissue remodelling. Programmed cell death (PCD) is a critical link between these disturbances and progressive structural failure. Apoptosis, pyroptosis, necroptosis, ferroptosis and autophagy-associated cell-fate regulation rarely operate independently. Their activation and biological consequences are determined by cell type, anatomical niche, disease stage and stress intensity. However, the concurrent detection of multiple death-associated markers is often misinterpreted as mechanistic crosstalk, hindering accurate identification of causal pathways and therapeutic targets. This Review proposes an evidence-graded, disease-stage-, cell-type- and microenvironment-dependent framework for interpreting PCD interactions in OA, IVDD and OP. It distinguishes shared upstream triggers, convergent regulatory nodes, sequential transitions, direct molecular conversion and functional coexistence according to their evidential strength. We further evaluate therapeutic strategies targeting the cell death–inflammation–metabolism axis, including multi-target agents, nanomaterials, extracellular vesicles, biomaterials and tissue engineering. Most evidence remains preclinical, underscoring the urgent need for human validation, causal target confirmation and rigorous assessment of delivery, durability, safety and manufacturability. This framework may improve mechanistic precision and accelerate the development of context-specific therapies for degenerative skeletal diseases.
BackgroundPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with progressive peribiliary inflammation and fibrosis. Disease-modifying therapies are lacking, and the cell-type-specific mechanisms linking genetic susceptibility to pathogenic immune states remain incompletely understood.MethodsWe performed a transcriptome-wide association study (TWAS) using PSC GWAS summary statistics and GTEx v8 liver eQTL weights. TWAS-prioritized genes were mapped onto a PSC liver single-cell RNA-seq atlas (GSE247128) using integrated gene set scoring (irGSEA). Monocyte/macrophage subsets were re-clustered and lipid-associated macrophages (LAMs) were stratified by TWAS activity. Core genes distinguishing high-versus low-activity LAMs were identified using seven machine-learning feature selection algorithms. JAML was validated in bulk transcriptomic cohorts (GSE119600, GSE177044), evaluated by immune infiltration analysis, examined by cell–cell communication inference (CellChat), assessed by virtual knockout (scTenifoldKnk), and spatially localized using Visium FFPE spatial transcriptomics (PSC: GSE245620; control: GSE240429), and validated at the protein level using Western blot and ELISA in an in vitro macrophage model.ResultsTWAS activity was predominantly enriched in the monocyte/macrophage lineage. Within this lineage, LAMs (TREM2+ GPNMB+ APOC1+) showed the highest TWAS activity and occupied late pseudotime states. High-activity LAMs were enriched in fibrosis-related pathways (e.g., TGF-β, NOTCH, WNT/β-catenin) and innate immune pathways (e.g., TLR2/4-MAPK, NLRP3 inflammasome). Multi-algorithm feature selection identified JAML (AMICA1) as a core discriminator of high-versus low-activity LAMs. JAML was upregulated in PSC in bulk cohorts, associated with higher macrophage and lower activated CD8+ T-cell infiltration, showed enhanced cell–cell communication signatures, and spatially co-localized with LAM and fibrosis scores in PSC tissue sections. In vitro, JAML upregulation accompanied NF-κB p65 phosphorylation and PD-L1 expression in LPS/IL-6-stimulated macrophages, and JAML knockdown attenuated these responses.ConclusionIntegrating TWAS with single-cell and spatial transcriptomics highlights a genetically linked, highly active LAM state in PSC and nominates JAML + LAMs as a testable effector population potentially connecting genetic susceptibility to peribiliary fibrosis, with in vitro evidence supporting a JAML/NF-κB/PD-L1 inflammatory axis.
The brain relies on cerebrospinal fluid (CSF) and the glymphatic system to maintain its delicate internal environment. We explored through a literature search the complex interplay and circadian regulation of CSF production and glymphatic system exchanges attempting to delineate an integrated and innovative view of their activities. We focused on how biological clocks, present at various levels of the finely tuned CSF/interstitial fluid/glymphatic exchange chain, orchestrate these activities. A key aspect is exploring their relationship with the neurovascular unit (NVU), which acts as a crucial regulator of fluidic control and exchanges at the neuron/astrocyte/endothelium interface. While the daily cycling activity of the glymphatic waste system is supported by increasing experimental evidence in animal models, the precise coordination and the primary location of the underlying biological clocks remain subjects of ongoing discussion. We provided a comprehensive discussion addressing these unanswered questions regarding the synchronization and primary regulatory mechanisms governing brain fluid dynamics. Understanding the circadian orchestration of CSF and glymphatic system activities, and their intricate connections with the NVU, is paramount for comprehending brain homeostasis and disease. Further research into the precise localization and function of these biological clocks is crucial for advancing our knowledge of brain fluid dynamics.
BackgroundRadiation-induced renal injury (RRI) is characterized by a prolonged latent phase from radiation exposure to clinical dysfunction. Conventional markers such as serum creatinine and blood urea nitrogen (BUN) may only increase after substantial nephron loss, thereby missing a critical therapeutic window during which renal injury may remain amenable to mitigation.ObjectiveThis review synthesizes emerging strategies for the early, pre-fibrotic detection of RRI, emphasizing molecular damage biomarkers, genomic and epigenetic indicators, and advanced functional imaging techniques that may identify subclinical abnormalities before irreversible fibrosis develops.ContentTubular damage biomarkers such as kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) provide sensitive signals that precede functional decline. Filtration markers such as cystatin C may improve early risk stratification compared with creatinine alone. Genomic indicators, including γ-H2AX foci and circulating or urinary microRNAs such as miR-21 and miR-29 capture DNA damage and fibrotic signaling transitions. Advanced imaging modalities—particularly non-contrast multiparametric MRI (diffusion-weighted imaging/intravoxel incoherent motion, arterial spin labeling, blood oxygen level–dependent MRI, and T1 mapping)—demonstrate strong correlations with biopsy-proven fibrosis and microvascular dysfunction. Tc-99m MAG3 renography further reveals split renal function and asymmetrical injury masked by preserved contralateral reserve.ConclusionEvidence supporting these candidate approaches in human radiation-induced renal injury remains limited. Tubular biomarkers, cystatin C, genomic indicators, urinary extracellular-vesicle signatures, and multiparametric MRI have demonstrated potential in other renal disorders or preclinical radiation models, but their RRI-specific kinetics, thresholds, sensitivity, and specificity remain insufficiently established. We therefore propose a multimodal research framework integrating radiation exposure and renal dosimetry, serial renal function assessment, candidate biofluid biomarkers, and functional imaging. Prospective longitudinal validation is required before this framework can be used for routine clinical diagnosis or treatment selection.
sFRP2, a member of the secreted frizzled-related protein family, is an extracellular protein characterized by a cysteine-rich domain and a netrin-like (NTR) domain. By modulating ligand availability, receptor selection, and microenvironmental signal integration, sFRP2 exerts highly context-dependent biological effects. Accumulating evidence suggests that sFRP2 should no longer be viewed merely as a WNT antagonist, but rather as an extracellular regulatory molecule that links development, tissue repair, and pathological remodeling. This review summarizes the molecular structure, expression patterns, and functional duality of sFRP2, with particular emphasis on its roles in regulating canonical and non-canonical WNT signaling, coordinating receptor bias and receptor switching, and participating in TGF-β-driven fibrosis, CXADR/NO-mediated WNT-independent growth control, endoplasmic reticulum stress-associated repair, and metabolic inflammation. We further discuss its functions within the tumor microenvironment, including the modulation of angiogenesis, cancer-associated fibroblasts, immunosuppression, and tumor cell survival. By integrating receptor bias and receptor switching with WNT-independent signaling, this review extends beyond a predominantly WNT-centered view of sFRP2 and proposes a context-stratified framework for biomarker interpretation and therapeutic targeting based on cellular origin, dominant signaling axis, disease stage, and tissue compartment.
Osteoporosis is a systemic skeletal disorder characterised by reduced bone mass, microarchitectural deterioration and increased fracture risk. Its pathogenesis extends beyond an imbalance between bone formation and resorption and involves osteoimmune dysregulation, vascular insufficiency, oxidative and inflammatory stress, and altered mechanical signalling within the bone microenvironment. Conventional two-dimensional cultures cannot adequately reproduce the three-dimensional matrix organisation, spatial multicellular interactions and mechanical properties of bone tissue, whereas animal models are limited by species-specific differences in bone remodelling, immune regulation and disease progression. Bone organoids integrating human stem/progenitor cells, bone-resident cells, immune and endothelial components, biomimetic matrices and dynamic culture systems provide a promising intermediate platform for modelling osteoporosis-related microenvironmental dysfunction. Unlike previous reviews that broadly summarised bone organoid construction and applications across skeletal diseases, this review focuses specifically on osteoporosis and proposes a mechanism–module–functional readout framework. This framework translates osteogenic suppression, RANKL/RANK/OPG-mediated osteoclast activation, immune–inflammatory amplification, vascular impairment and mechanical unloading into selectable organoid modules with measurable endpoints, including matrix formation, mineralisation, osteoclast resorption, inflammatory and oxidative-stress responses, vascular network function and mechanosensitive signalling. We further discuss how these models could connect candidate molecular signals with human-relevant three-dimensional functional phenotypes, thereby supporting biomarker discovery, drug-response assessment and patient stratification. However, organoid-derived candidates should not be regarded as clinically validated biomarkers without confirmation in independent patient cohorts and prospective clinical studies. Standardised construction, reproducible quality control, functional maturation and clinically anchored validation will therefore be essential for advancing osteoporosis-related bone organoids from experimental disease models towards biomarker translation and precision medicine.
BackgroundSuccinylation-linked metabolic rewiring and neutrophil-driven inflammation are key drivers of colorectal carcinoma (COAD) progression; however, they have rarely been translated to an end-to-end artificial intelligence (AI) drug-design pipeline connecting target nomination, resistance-relevant tumor microenvironment states, and candidate evaluation.MethodsWe integrated bulk transcriptomes from The Cancer Genome Atlas colon adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus databases to derive succinylation–neutrophil (SN)-associated genes using the limma package, single-sample gene-set enrichment analysis, weighted gene coexpression network analysis, and protein–protein interaction network analysis; we then constructed a cross-cohort prognostic system by screening and selecting the machine-learning combination of random survival forest and ridge regression as the optimal predictor. To enable precision stratification, we applied deep-learning self-organizing maps (SOMs) to define the SN-driven molecular subtypes and characterized their immune and pathway heterogeneities at both bulk and single-cell resolutions through AI-powered virtual perturbation analysis to interrogate the cell-state shifts. Importantly, we extended AI approaches in drug design beyond risk modeling to a target-to-candidate workflow by nominating a druggable SN hub gene. We also performed co-culture in vitro assays for identifying NOX4 molecular insights into neutrophil patterns and their associations with COAD progression.ResultsOur approach identifies SN biology as a clinically actionable axis in COAD, highlights NOX4 as a central SN-associated target with immune relevance, and prioritizes talazoparib as a repurposing candidate supported by integrated in silico evidence.ConclusionThe findings of this study provide a precision-oncology blueprint that couples AI stratification with therapeutic nomination and evaluation.
