The blood–spinal cord barrier (BSCB) is a specialized vascular interface that preserves spinal cord homeostasis by regulating molecular and cellular trafficking between blood and neural tissue. Disruption of BSCB integrity is a critical pathological event follow-ing spinal cord injury (SCI), leading to increased permeability, inflammatory cell infil-tration, and secondary neurodegeneration. Increasing evidence indicates that BSCB breakdown is not a single event but a dynamic, time-dependent process. In this review, we summarize the molecular and cellular mechanisms responsible for BSCB disruption after SCI in a chronological manner. Key pathological events occurring during the acute, subacute, and chronic phases are discussed, including pathological hemody-namic changes, endothelial stress responses, epigenetic regulation, inflammatory me-diators, immune cell–endothelial interactions, and extracellular matrix remodeling. We further highlight endogenous protective and reparative mechanisms that emerge at later stages. A comprehensive understanding of the temporal characteristics of BSCB disruption may facilitate the development of phase-specific therapeutic strate-gies aimed at preserving barrier integrity, limiting secondary injury, and improving neurological recovery after SCI. This temporal perspective underscores the need for stage-specific interventions to preserve BSCB integrity and improve outcomes after SCI.

Spinal cord injury (SCI) causes severe energy metabolism dysfunction, hindering neuronal survival and recovery. Adipose tissue-derived stromal cells (ADSCs) have neuroprotective potential, but their role in regulating neuronal energy metabolism and the underlying mechanisms remain unclear. This study aimed to investigate whether ADSCs are capable of restoring neuronal glycolysis through the FOXK1-HK2 signaling pathway, thereby replenishing the energy supply and facilitating tissue regeneration. We employed rat and cell models of SCI to observe the effects of ADSCs on glycolytic metabolism and apoptosis. Transcriptome sequencing identified glycolysis-related differentially expressed genes. Lactate detection and Seahorse assays were used to quantify glycolytic activity. Dual-luciferase reporter assays verified the FOXK1-HK2 regulatory relationship. Cut Run assay provided direct evidence of FOXK1 binding to the HK2 promoter. Behavioral tests, histopathological staining and immunofluorescence were used to evaluate in vivo functional recovery and tissue repair. FOXK1 knockdown confirmed its role in the ADSC-mediated pathway. We found that ADSCs exerted multiple protective and regulatory effects on neurons and motor function. Specifically, they strongly inhibited neuronal oxidative stress, protected mitochondria, and promoted neuronal metabolic reprogramming. Additionally, ADSCs increased glycolytic activity and lactate production, which further contributed to promoting neuronal survival and the recovery of hindlimb motor function. Blocking TGF-β1 signaling abrogated ADSC-induced activation of the FOXK1-HK2 axis and subsequent enhancement of glycolysis, confirming TGF-β1 as a critical paracrine mediator. Through interaction with HK2, FOXK1 plays a critical role in modulating glycolysis. Dual-luciferase reporter and Cut Run assays confirmed that FOXK1 regulates the HK2 promoter, thereby increasing its transcriptional activity. The inhibition of FOXK1 expression resulted in suppressed HK2 expression, reduced glycolytic flux, and weakened the neuroprotective effects of ADSCs on SCI. ADSCs are considered a potential option for SCI treatment, and their therapeutic effects are closely related to the FOXK1/HK2 axis, which mediates ADSCs’ regulation of neuronal glycolytic metabolism to exert protective and reparative functions.

Ferroptosis plays an essential role in tumor progression. Therapeutic agents targeting ferroptosis emerge as a novel strategy for cancer treatment. Abnormal amino acid metabolism can control ferroptosis sensitivity in cancer cells, and lead to the deficiency or accumulation of specific products in the tumor microenvironment (TME). Here, we demonstrated that 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced growth inhibition in gastric cancer cell lines, primary gastric cancer mouse models, and patient-derived tumor organoids. DMNQ exerted ferroptosis inducing effects by inhibiting STAT3 phosphorylation and transcriptional activity. Importantly, the STAT3/SLC1A4 axis regulated cysteine uptake, tumor killing by T cells and the efficacy of anti-PD-L1 immunotherapy. Collectively, our findings revealed a critical mechanism by which DMNQ exerts a significant anti-cancer role in gastric cancer through increasing ferroptosis to enhance cancer immunotherapy and may provide a novel therapeutic strategy for gastric cancer.

Spinal cord injury (SCI) triggers persistent neuroinflammation, primarily driven by aberrant astrocyte activation, which exacerbates secondary neurodegeneration. Indole-3-propionic acid (IPA), a tryptophan-derived metabolite produced by the gut microbiota, has recently emerged as a potent anti-inflammatory agent in neurological disorders. However, its therapeutic potential and underlying mechanisms in SCI remain unexplored. In this research, using a TNF-α-stimulated astrocyte model in vitro and a mouse SCI model in vivo, we demonstrated that IPA significantly attenuated the expression of pro-inflammatory mediators (IL-6, IL-1β, iNOS, COX-2, CCL2, CXCL2, CXCL10) in astrocytes, both in vitro and in vivo. Transcriptomic and mechanistic investigations reveal that IPA suppressed NF-κB/MAPK signaling pathways by activating the aryl hydrocarbon receptor (AhR). In SCI mice, IPA treatment reduced glial scar formation, enhanced neuronal survival, and improved long-term motor function, as evidenced by increased BMS scores, inclined plane test performance, and gait coordination. MRI and histopathological analyses further confirmed reduced lesion volume and preserved tissue integrity. Our findings demonstrate that gut microbiota-derived IPA acts through the AhR/NF-κB/MAPK axis to mitigate secondary spinal cord injury by exerting anti-inflammatory and neuroprotective effects. This work not only provides novel pharmacological insights into a metabolite-based approach for SCI treatment but also establishes IPA as a promising endogenous metabolite therapy with high translational potential.

Introduction:Osteosarcoma (OS) is the most prevalent primary bone malignancy in children and adolescents. Bioinformatics analyses have identified ANT1 (encoded by SLC25A4) as part of a gene cluster implicated in the development and progression of osteosarcoma. Authors of this study investigated the expression of ANT1/SLC25A4 in clinical specimens and established OS cell lines to evaluate its potential as a prognostic biomarker and its mechanistic role in OS pathogenesis. Methods:Immunohistochemical (IHC) analysis of ANT1 expression was performed on 63 archived human OS tissue sections (IRB-exempt). To assess functional impact, commercial MG-63 and HOS osteosarcoma cell lines were genetically modified to achieve SLC25A4 overexpression or knockdown. Cellular behavior was evaluated using proliferation, scratch wound-healing, and transwell invasion assays. In vitro numerical data were analyzed using one-way ANOVA with the LSD method for post hoc multiple comparisons. Correlations with clinical prognostic indicators were assessed using bivariate correlation analysis (SPSS v.22). Results:IHC staining revealed that most clinical OS specimens (48/63) exhibited significantly diminished ANT1 expression compared with normal periosteal tissue. In vitro, SLC25A4 knockdown significantly accelerated cell proliferation. Conversely, SLC25A4 overexpression significantly inhibited cell migration and invasion (p <0.05) compared with controls. Conclusions:Our findings demonstrate that ANT1/SLC25A4 frequently is downregulated in clinical OS, and that its restoration suppresses aggressive cellular phenotypes in vitro. These results suggest that SLC25A4 may function as a tumor suppressor in osteosarcoma. Further research is needed to correlate SLC25A4 expression with patient survival and to define the underlying molecular pathways.

Microglia play a crucial role in the progression of neuroinflammation following traumatic brain injury (TBI). Interleukin-3 (IL-3), a significant regulatory factor, has been involved in the pathogenesis of various diseases, yet its effects on neuroinflammation post-TBI through microglia remain unclear. Here, we evaluate the potential of IL-3 to alleviate neuroinflammation in microglia following TBI. Using the ABplex Multi-Metric Streaming Joint Analysis to detect inflammatory factors, we observed significantly elevated levels of IL-3 in cerebrospinal fluid, but not in blood samples, of patients with headaches and TBI. In addition, we found that administration of exogenous IL-3 within the brain reduced neuroinflammation and promoted functional recovery in rat TBI models. Mechanistically, we identified Peroxiredoxin-1 (PRDX1) as the target of IL-3 in microglia. Notably, the protective effects of IL-3 in TBI rats were abolished when PRDX1 was specifically knocked down in microglia. In conclusion, our experimental research demonstrates that IL-3 acts as a key modulator via regulating microglia polarization to inhibit neuroinflammation. IL-3 improves neurological function and prognosis in TBI rats by recruiting PRDX1 through IL-3R to modulate microglia polarization. Therefore, IL-3 may represent a novel therapeutic strategy for TBI.

Spinal cord injury (SCI) triggers a cascade of primary and secondary pathological events that culminate in the formation of glial and fibrotic scars, which constitute a major barrier to axonal regeneration and functional recovery. Emerging evidence highlights mitochondrial dysfunction as a central driver of this process. Mitochondria are essential for sustaining ATP production, maintaining redox balance, and regulating calcium homeostasis. Following SCI, direct mechanical disruption, oxidative stress, and calcium overload impair mitochondrial integrity, leading to energy metabolism collapse, excessive reactive oxygen species (ROS) accumulation, and disrupted mitochondrial dynamics. These alterations promote reactive gliosis, fibroblast activation, and maladaptive extracellular matrix deposition. Furthermore, defective mitophagy amplifies neuroinflammation and glial scar consolidation through the PINK1/Parkin and BNIP3/NIX pathways. Recent advances in mitochondrial-targeted therapies—including antioxidants (MitoQ, SS-31), metabolic modulators (AMPK agonists, NAD+ precursors), and strategies enhancing fusion or mitophagy—have demonstrated promising results in reducing scar formation and promoting neural repair. In addition, cutting-edge approaches such as mitochondrial transplantation, stem cell-derived mitochondrial transfer, and CRISPR-based mitochondrial gene editing provide new opportunities for restoring mitochondrial homeostasis. This review summarizes the multifaceted roles of mitochondrial dysfunction in SCI-induced scar formation and discusses novel therapeutic strategies targeting mitochondrial metabolism and dynamics to enhance neural regeneration.

Secondary injury following spinal cord injury (SCI) is a key factor leading to neurological dysfunction, yet effective clinical interventions remain lacking. In this study, we developed an injectable, reactive oxygen species (ROS)-responsive composite hydrogel (CeO2@OPP), comprising cerium oxide (CeO2) nanozymes embedded in an oxidized alginate/polyvinyl alcohol matrix crosslinked through dynamic boronate ester bonds. The hydrogel exhibits robust adhesiveness, effectively mitigating local hemorrhage and preventing pathological iron accumulation in injured cells. Notably, the hydrogel enables the on-demand release of CeO2 nanozymes through ROS-triggered hydrogel degradation, achieving sustained scavenging of ROS and alleviation of oxidative stress in the lesion microenvironment. In parallel, the calcium-chelating ability of the hydrogel matrix attenuates excitotoxic stress and restores mitochondrial function. These processes synergetically achieve self-treatment by inhibiting the ferroptosis of neurocytes. In a mouse SCI model, CeO2@OPP treatment promoted neural regeneration and synaptic remodeling, ultimately leading to a significant improvement in motor function. This facile and biocompatible therapeutic platform provides a purpose-driven strategy to intercept ferroptosis-associated secondary damage after SCI and presents a promising approach for translational intervention in central nervous system repair.

Spinal cord injury (SCI) represents a severe neurological disorder characterized by complex pathophysiological cascades, frequently resulting in irreversible sensorimotor deficits. A hallmark of this condition is the dual-phase response of glial and fibrotic scars: initially, reactive astrocytes and fibroblast-like cells form protective barriers that limit inflammatory spread and stabilize tissue integrity, yet chronically, these scars transition into inhibitory structures through excessive deposition of chondroitin sulfate proteoglycans (CSPGs) and collagen-rich extracellular matrix (ECM), obstructing axonal regeneration. Critically, these scars operate within an integrated SCI scar microenvironment, where multiple cellular, molecular, and matrix components dynamically and coordinately modulate their reparative-to-pathological shift. This review systematically examines the spatiotemporal organization, cellular heterogeneity, and molecular drivers underlying scar duality. We evaluate bidirectional interactions between glial and fibrotic components and non-scar elements. Notably, the scar microenvironment serves as a pivotal regulatory hub that dictates the switch between the protective and inhibitory phenotypes of scars post-SCI. This work underscores the scar microenvironment's centrality in SCI pathology and advances the conceptual framework for developing precision therapies to overcome neuroregenerative failure.The Translational Potential of this Article: This review's spinal cord injury scar microenvironment theory delivers a transformative translational framework. It captures spatiotemporal crosstalk of cellular, molecular, and matrix components across injury phases, replacing fragmented single-target interventions. Representative translational strategies include artificial spinal cord ECM hydrogels, Induced Pluripotent Stem Cells (iPSCs) derived spinal cord organoid transplantation, exosome-mediated epigenetic regulation, among others, which are all aligned with pathological progression. Supported by international Phase I/II clinical trials targeting scar microenvironment components, this theory integrates basic research with clinical needs. It enables precision SCI therapy through coordinated intervention logic, accelerating the translation from symptomatic management to curative neural repair.

BACKGROUND:Osteoporosis is a serious bone disease, it can eventually lead to disability. However, no safe or effective intervention is currently available. Therefore, there is an urgent need to develop effective drugs that reduce bone loss and treat osteoporosis. PURPOSE:This study aimed to ascertain the potential of ailanthone (AIL), a natural small molecule, as a therapeutic drug for alleviating the progression of osteoporosis. METHODS:By screening of a library of natural compounds; in vitro assays for examining the inhibition of osteoclast differentiation by AIL: in vivo assays for detecting the anti-osteoclastogenesis activity of AIL using mimicking progressive bone loss mice model and the other simulating postmenopausal osteoporosis mice model. Identification and characterisation of the binding of AIL to extracellular signal-regulated kinase 2 (ERK2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, microscale thermophoresis; various assays for examining the dependence of AIL's anti-osteoclastogenesis activity on ERK2. RESULTS:This study discovered AIL, a potent inhibitor of osteoclastogenesis from a screened library of natural compounds. In vitro studies demonstrated that AIL attenuated RANKL-induced osteoclast differentiation. Additionally, AIL administration decreased osteoclast populations and their bone-degrading activities. AIL was discovered to target ERK2, specifically the Methionine-108 (Met-108) site, which is presumed to contribute to its anti-osteoclastogenic properties. Further analysis indicated that AIL blocks ERK1/2 phosphorylation, thereby influencing the NF-κB signaling cascade. CONCLUSIONS:Collectively, these findings demonstrate AIL, that can significantly inhibit osteoclastogenesis linked to inflammaging, opening up novel avenues for osteoporosis treatment strategies and other ERK related diseases.

This study employed transcriptome sequencing and targeted metabolomics to delve into the molecular alterations in mouse spinal cords following spinal cord injury (SCI). Notably, a significant depletion of pantothenic acid (PA) was observed in the injured spinal cord, exhibiting an inverse correlation with microglial inflammation and activation. To further elucidate this relationship, experimental interventions using PA were conducted in SCI mouse models. The results demonstrated that PA administration effectively inhibited microglial inflammation via modulation of the JAK2/STAT3 signaling pathway. This inhibition not only mitigated the neuroinflammatory milieu but also fostered an environment conducive to axonal growth and neuronal regeneration. Consequently, SCI mice treated with PA exhibited improved motor function recovery compared to untreated controls. Our findings not only deepen the understanding of the relationship between PA and neuroinflammatory processes in SCI but also highlight the therapeutic potential of PA in promoting neuronal regeneration and functional recovery.

With the development of metabolic engineering, increasing requirements for efficient microbial biosynthesis call for establishment of multi-strain co-culture system. Dynamic regulation of population ratios is crucial for optimizing bioproduction performance. Optogenetic systems with high universality and flexibility have the potential to realize dynamic control of population proportion. In this study, we utilized an optimized chromatic acclimation sensor/regulator (CcaS/R) system and a blue light-activated YF1-FixJ-PhlF system as induction modules. A pair of orthogonal quorum sensing systems and a toxin-antitoxin system were employed as communication module and effector module, respectively. By integrating these modules, we developed a dual light-controlled co-culture system that enables dynamic regulation of population ratios. This co-culture system provides a universal toolkit for applications in metabolic engineering and synthetic biology.

The recent discovery of cell death mediated by metal ions has aroused significant interest in harnessing this novel mechanism of cell death for cancer therapy. As the two identified metal ion-based regulated cell death forms, ferroptosis and cuproptosis were initially studied separately, while increasing evidences underscored their intricate connections. Gastric cancer (GC) is one of the most severe malignant tumors of the digestive system. Targeting the complex interplay between ferroptosis and cuproptosis, and understanding their intrinsic mechanisms may offer approaches for developing innovative therapies in GC. Here, we identified that metal-regulatory transcription factor 1 (MTF1) was the key gene blocking the sensitivity of ferroptosis and cuproptosis enhanced by the combination treatment with FINO2 and ES-Cu in vitro and in vivo. Mechanistically, MTF1 suppressed FINO2/ES-Cu induced ferroptosis through upregulating FTH1 to reduce Fe2+ levels. In addition to direct transcriptional upregulation of FTH1, MTF1 activated TRIM31. Subsequently, TRIM31 catalyzed ubiquitination of NCOA4 and also promoted the expression of FTH1. On the other hand, it also activated iron-sulfur cluster assembly 2 (ISCA2)-mediated iron-sulfur cluster (ISC) assembly and iron starvation response to inhibit cuproptosis and ferroptosis. Collectively, our findings indicated the mechanism of the synergistic effect of ferroptosis and cuproptosis in the treatment of GC and presented a prospective therapeutic strategy through elucidating the molecular mechanism of ferroptosis and cuproptosis mediated by MTF1.

Helicobacter pylori (H. pylori) infection mediates activation of oncogenes and inhibition of tumor suppressor genes through aberrant DNA methylation, which is the predominant risk factor for gastric tumorigenesis. Here, by integrating transcriptome and epigenetic multi-omics analyses of gastric tissues and mouse models, we identified that inhibitor of differentiation 4 (ID4) was downregulated in H. pylori-infected gastric tissues and associated with prognosis of gastric cancer (GC). H. pylori infection remarkably increased the methylation level of the ID4 promoter region in the GC patients and mouse models. ID4 served as a tumor suppressor gene in GC and was required for H. pylori-mediated tumorigenic activities in vitro cellular and in vivo tumor-bearing mouse models. Moreover, H. pylori infection induced DNMT3B upregulation through recruiting KLF5 to its promoter and further promoted ID4 DNA methylation modification. Notably, ID4 formed heterodimers with the basic HLH transcription factors DEC1 to inhibit its transcriptional activity; therefore, downregulation of ID4 promoted SHH/GLI1 signaling through a DEC1 dependent transcriptional modulation. Collectively, our findings indicate H. pylori infection depends on DNMT3B to induce ID4 DNA methylation and ID4 promoter hypermethylation status is a potential biomarker to identify GC. Loss of ID4 could be a key component of H. pylori-mediated gastric tumorigenesis through dysregulation of DEC1/SHH/GLI1 axis, which provides potential therapeutic targets in GC.

ABSTRACT Glucocorticoids (GCs) are steroid hormones commonly used to treat inflammation, autoimmune diseases, and malignant tumors. By inhibiting bone formation and promoting osteoclast apoptosis, GCs significantly accelerate the onset of femoral head osteonecrosis, leading to structural changes, collapse, or destruction of bone. The mechanisms and pathways involved in glucocorticoid‐induced osteonecrosis (GION) may offer insights for developing new treatments. The pathogenesis of GION is complex and multifaceted, involving multiple pro‐apoptotic signaling pathways that collectively drive bone degradation and osteonecrosis. Specifically, key pathways implicated in GION, including 11β‐HSD enzymes, CD95/CD95L, STAT1‐caspase 3, the Bcl‐2 subfamily, PI3K/Akt, and Wnt/β‐Catenin, represent potential therapeutic targets for preventing and treating GION.

Treatment for spinal cord injuries (SCIs) remains largely ineffective, with scar formation and neural degeneration being major barriers to functional recovery. Neonatal microglia have shown potential in reducing scar formation and promoting axonal regrowth. However, cell viability and retention at the injury site are often suboptimal. The hostile post-SCI inflammatory microenvironment leads to poor cell survival and the dural damage that is frequently associated with SCIs results in cell loss. To address these challenges, we have developed an albumin-based hydrogel. This hydrogel creates a favorable microenvironment for the encapsulated cells, mimicking the extracellular matrix and enhancing the viability of the transplanted cells. In vivo studies demonstrate its efficacy in preventing scar formation, promoting axonal regeneration, and sealing the dura. Importantly, this hydrogel leverages albumin, a natural polymer in the body, and is synthesized through a simple process, making it highly feasible for clinical translation. In summary, this albumin hydrogel is a valuable delivery vehicle that enhances the therapeutic potential of neonatal microglia in treating SCIs, particularly those involving dural rupture.

Cartilage metabolism balance chaos is crucial in the development and progression of osteoarthritis (OA), with chronic low-grade inflammation being the primary factor that leads to chondrocyte metabolic dysregulation. Fexofenadine (FFD) is a widely used commercially available anti-allergy compound, which has been shown to reduce inflammation. The present study finds FFD’s therapeutic effects in primary human ex-vivo cultures and surgically induced murine models. Mechanism study illustrates FFD exhibits chondroprotective effect through anti-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammation and pro-Transforming Growth Factor Beta (TGFβ)-associated anabolism. Specifically, FFD directly binds to cytosolic phospholipase A2 (cPLA2), down-regulating downstream NF-κB activation, resulting in alleviated catabolism. Notably, Signal Transducer and Activator of Transcription 1 (STAT1) is first identified as FFD’s target by Drug affinity responsive target stability which shows the Gln-314 site is required. FFD blocks STAT1 binds to TGF-β type I receptor, leading to secondary SMAD Family Member 2 (Smad2) phorsphorylation, slightly enhances chondrocyte proliferation and matrix production. Importantly, further study demonstrates FFD directly binds Smad2 by the target proteins fishing technique, remarkably active TGFβ-related biological process. These findings provide new insights into the chondroprotective role of FFD with novel target and downstream pathway, offering promising avenues for the treatment of OA.

Astrocytes undergo a reactive transformation in central nervous system (CNS) disorders, manifesting significant heterogeneity in morphology, molecules, function, and spatial distribution. Just like all cells, astrocytes necessitate energy for their basic functions. Energy production proves critical for the survival and development of astrocytes, as well as their fate determination and functional diversity. The activation process of astrocytes involves a metabolic shift in energy, yet our understanding of how this change impacts the heterogeneity of reactive astrocytes remains limited. In this comprehensive review, we begin by outlining the advancements in research on reactive astrocytes in CNS disorders, establishing a crucial association between the energy metabolism of reactive astrocytes and their molecular and functional aspects. Following this, we delve into a thorough analysis of the energy metabolic transitions of reactive astrocytes within the context of CNS diseases. Starting from the essential pathways of energy metabolism, we present a novel perspective, shedding light on the molecular and functional heterogeneity of reactive astrocytes by considering the heterogeneity in energy metabolism. In conclusion, we propose that the modulation of energy metabolism in reactive astrocytes, coupled with the promotion of their functionality toward disease recovery, represents a cutting-edge and promising strategy for the treatment of CNS diseases.