Supplementary Table S3 shows UCSC-predicted transcription factors that bind to CKB promoters.

Tumor-infiltrating CD8+ T cells undergo aberrant lipid accumulation in the tumor microenvironment (TME), which triggers ferroptosis, drives T cell dysfunction, and impairs anti-tumor activity. However, strategies to protect the effector functions of CD8+ T cells by preventing ferroptosis in vivo remain limited. Here, we report that menaquinone-4 (MK-4), a form of vitamin K2, serves as a potent ferroptosis inhibitor that preserves CD8+ T cell function within the TME and enhances anti-tumor activity. Specifically, we demonstrated that MK-4 acts as a potent anti-ferroptotic agent in CD8+ T cells, thereby restoring their effector cytotoxic potential. RNA sequencing (RNA-seq) analysis revealed that MK-4 reprograms the transcriptional landscape of CD8+ T cells by reversing RSL3-induced ferroptosis-related gene expression, restoring effector-associated gene expression, and mitigating dysfunction and exhaustion programs. In adoptive cell transfer models, MK-4 pretreatment effectively suppressed ferroptosis in CD8+ T cells, enhanced their effector functions, and inhibited tumor growth. Similarly, intravenous injection of MK-4 attenuated ferroptosis in endogenous CD8+ T cells and strengthened their anti-tumor capacity. Furthermore, the combination of MK-4 with anti-programmed death-1 (PD-1) antibody therapy elicits a synergistic anti-tumor effect. Collectively, our findings reveal that MK-4 preserves CD8+ T cell function by inhibiting ferroptosis, boosts anti-tumor immunity, thereby highlighting its potential as a therapeutic strategy for cancer treatment.

Supplementary Table S1 shows PCr IHC staining score in human glioma microarray.

Supplementary Table S2 shows CKB IHC staining score in human glioma microarray.

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.

Ethnopharmacological relevance: Shenqi Yanshen Decoction (SQYSD) is a traditional Chinese herbal formula clinically used for chronic kidney disorders and kidney-related bone complications under the traditional concept that “the kidney governs bone.” However, experimental evidence demonstrating its coordinated protective effects on renal and skeletal injury in chronic kidney disease–mineral and bone disorder (CKD-MBD) remains limited.Aim of the study: This study aimed to evaluate the therapeutic effects of SQYSD on renal dysfunction, mineral metabolism disorder, and bone injury in CKD-MBD, and to explore whether its actions are associated with regulation of Wnt5a/RhoA/Pkn3-mediated osteoclast activation.Materials and methods: The chemical profile of SQYSD was characterized by UPLC-Q/TOF-MS, and representative constituents were quantified by UPLC-MS/MS. A CKD-MBD mouse model was established by 5/6 nephrectomy combined with a low-calcium, high-phosphate diet. Mice were orally treated with SQYSD for 10 weeks, with cinacalcet hydrochloride used as a clinically relevant positive control. Renal function, calcium–phosphate metabolism, and bone turnover markers were assessed biochemically. Renal and femoral pathological changes were evaluated by histological staining, transmission electron microscopy, and micro-computed tomography. Transcriptomic analysis, qPCR, Western blotting, immunofluorescence, and immunohistochemistry were performed to investigate potential mechanisms. RANKL-induced osteoclast differentiation in RAW264.7 cells, together with Wnt5a overexpression, was used for in vitro validation.Results:UPLC-Q/TOF-MS identified 71 phytochemicals in SQYSD, and 12 representative constituents were quantified, with icariin, epimedin B, chlorogenic acid, and epimedin A being abundant components. In CKD-MBD mice, SQYSD improved body weight, reduced serum creatinine and blood urea nitrogen levels, corrected calcium–phosphate imbalance, and attenuated renal inflammatory infiltration, fibrosis, calcification, and ultrastructural injury. SQYSD also alleviated bone deterioration, as evidenced by improved bone mineral density, BV/TV, trabecular number and thickness, reduced trabecular separation, restored bone turnover markers, and decreased osteoclast accumulation. Compared with cinacalcet, SQYSD showed broader protective effects on both renal and skeletal lesions. Transcriptomic analysis indicated that SQYSD markedly regulated the Wnt signaling pathway, and subsequent validation showed that SQYSD suppressed Wnt5a/RhoA/Pkn3-related signaling in renal and bone tissues. In vitro, SQYSD inhibited RANKL-induced osteoclast differentiation and F-actin ring formation, accompanied by downregulation of Wnt5a, RhoA, Pkn3, and cytoskeleton-associated proteins. Wnt5a overexpression partially reversed the inhibitory effects of SQYSD on osteoclastogenesis.Conclusion:SQYSD exerts coordinated renal and skeletal protective effects in CKD-MBD, involving improvement of renal dysfunction, correction of mineral metabolic disorder, preservation of bone microarchitecture, and inhibition of osteoclast activation. These effects may be partly associated with suppression of Wnt5a/RhoA/Pkn3-related signaling. The findings provide pharmacological evidence supporting the traditional use of SQYSD in kidney-related bone disorders and suggest its potential as a complementary multi-target herbal intervention for CKD-MBD.

Supplementary Table S6 shows the sequences of shRNAs used in this study.

Supplementary Table S4 shows PCr and BRD2 IHC staining scores in the serial sections of human glioma microarrays.

The structural stabilization and conformational modulation of inflammatory targets such as TNF-[Formula: see text] and STAT3 are of great significance in the discovery of novel anti-inflammatory agents and provide valuable insights into ligand–protein interaction mechanisms at the molecular level. In this study, we employed an integrated in silico framework, including ensemble molecular docking, long-timescale molecular dynamics (MDs) simulations, and binding free energy calculations, to investigate the atomistic interaction mechanisms of two selected small molecules, isorhamnetin and 7-methoxy-2-methyl isoflavone, against TNF-[Formula: see text] and STAT3. Initial ensemble docking identified energetically favorable candidate binding poses across different receptor conformations. Subsequent 500 ns MD simulations suggested that these ligands may contribute to stabilization of the protein–ligand complexes and reduction of local structural fluctuations. Conformational dynamics analyses, including principal component analysis (PCA), free energy landscape (FEL), and dynamic cross-correlation matrix (DCCM), revealed ligand-associated changes in conformational convergence and altered intra-protein correlated motions. Furthermore, MM-PBSA calculations provided effective binding energy estimates (without entropic contributions), particularly for the STAT3–7-methoxy-2-methyl isoflavone complex ([Formula: see text] kJ/mol). These computational findings provide atomistic insights into the possible ligand-associated conformational stabilization mechanisms, offering a computational structural basis for targeting the TNF–STAT3 inflammatory axis.

Supplementary Figures S1 shows that GSCs produce high levels of phosphocreatine through upregulating CKB. Supplementary Figures S2 shows that ZEB1 promotes CKB transcription in GSCs. Supplementary Figures S3 shows that knockdown of CKB impedes GBM growth. Supplementary Figures S4 shows that disruption of phosphocreatine production impedes GBM growth. Supplementary Figures S5 shows that cCr treatment shows no side effect on mice. Supplementary Figures S6 shows that phosphocreatine binds to BRD2 and inhibits its ubiquitin mediated proteasomal degradation. Supplementary Figures S7 shows that phosphocreatine promotes chromosome segregation and GSC proliferation through BRD2 mediated transcription. Supplementary Figures S8 shows that disruption of phosphocreatine biosynthesis by cCr improves JQ1 therapeutic efficacy in GBM.

Supplementary Table S5 shows the detailed genetic mutations of four GBM cell lines.

Supplementary Table S7 shows the primer sequences used for Real-Time PCR.

The modulation of immune checkpoint activity exerts profound impacts on tumor immunotherapy. However, the interfere of mature immune checkpoints encounter efficacy challenges in solid tumors, which underlies a critical barrier in clinical translation of multiple potential targets. Herein, we propose a biochemical immune modulation strategy for immunosuppression reversal by blocking the mature of CD47 within the endoplasmic reticulum (ER). Clinically used radionuclides iodine-131 (131I) is reengineered to encapsulate within microporous barium titanate nanoparticles, forming an immunoactive nanomodulator. Leveraging polarized and collisional relaxation, the electrons emitted from 131I mediate continuous disulfide bond reduction, blocking CD47 folding and surface translocation, resulting in a 93.6% reduction in CD47 expression. Together with the remarkable increase of tumor antigen presentation induced by ER reductive stress in pancreatic tumor-bearing mice, we realize a 93% tumor inhibition and a 3-fold prolongation of survival. This work underscores the role of organellar biochemistry in reshaping immunosuppression for tumor immunotherapy.

Since the integration of Fenton chemistry into biomedicine, chemodynamic therapy (CDT) has rapidly emerged as a vibrant interdisciplinary research frontier. In recent years, exciting advances in both the fundamental understanding and the attractive applications of CDT have greatly enriched the field, expanding its conceptual boundaries and therapeutic potential. In this review, we first summarize the advances in CDT from a chemical perspective, including strategies to optimize reaction centers at the electronic level and approaches to refine reaction environments through cellular metabolic regulation. We then discuss emerging insights into hydroxyl radical (·OH)–mediated biological mechanisms and effects, including CDT‐related cell death pathways, newly identified subcellular therapeutic targets, and the growing applications of CDT in antibacterial therapy, wound healing, and immune activation. Furthermore, we summarize ongoing efforts toward clinical translation and outline key challenges and perspectives from a translational standpoint. More importantly, we propose an expanded conceptual framework for CDT in response to the evolving research landscape and present an outlook on the key scientific questions and promising application directions. We hope this review will benefit the disciplinary research paradigm across chemistry, nanotechnology, and biology, providing valuable inspiration for future research in nanomedicine.

The infiltration of glioblastoma multiforme (GBM) is predominantly characterized by diffuse spread, contributing significantly to therapy resistance and recurrence of GBM. In this study, we reveal that microtubule deacetylation, mediated through the downregulation of fibronectin type III and SPRY domain-containing 1 (FSD1), plays a pivotal role in promoting GBM diffuse infiltration. FSD1 directly interacts with histone deacetylase 6 (HDAC6) at its second catalytic domain, thereby impeding its deacetylase activity on α-tubulin and preventing microtubule deacetylation and depolymerization. This inhibitory interaction is disrupted upon phosphorylation of FSD1 at its Ser317 and Ser324 residues by activated CDK5, leading to FSD1 dissociation from microtubules and facilitating HDAC6-mediated α-tubulin deacetylation. Furthermore, increased expression of FSD1 or interference with FSD1 phosphorylation reduces microtubule deacetylation, suppresses invasion of GBM stem cells, and ultimately mitigates tumor infiltration in orthotopic GBM xenografts. Importantly, GBM tissues exhibit diminished levels of FSD1 expression, correlating with microtubule deacetylation and unfavorable clinical outcomes in GBM patients. These findings elucidate the mechanistic involvement of microtubule deacetylation in driving GBM cell invasion and offer potential avenues for managing GBM infiltration.

Cancer nanomedicine has emerged as a transformative approach in oncology, providing targeted therapeutic strategies with enhanced efficacy and reduced systemic toxicity. The integration of multi-omics technologies has further revolutionized this field.This review was conducted based on a systematic literature search using PubMed, Web of Science, and Scopus databases. Keywords included “cancer nanomedicine,” “multi-omics,” “precision oncology,” “nanoparticle,” and related terms. The search was limited to articles published between 2000 and 2024. Only English-language full-text articles reporting original research or clinical studies relevant to omics-enhanced nanomedicine were included. This review uniquely synthesizes recent advances in omics-enhanced nanomedicine, highlighting the integration of multi-omics data for precision cancer therapy. Key innovations include omics-driven nanoparticle design, patient stratification via biomarker panels, and synergy with immunotherapy. Future directions focus on AI-aided data integration and clinical translation.

Glioma intratumoral heterogeneity remains a critical barrier to effective treatment, driving recurrence and resistance to therapy. Emerging evidence suggests that glioma cells acquire neural-like features through paracrine and synaptic communication with neural cells, fostering functional diversity within tumors. While neuro-cancer interactions are implicated in glioma heterogeneity, their precise roles remain incompletely synthesized. Here, by consolidating these discoveries, a conceptual framework is proposed for understanding the glioma intratumoral heterogeneity shaped by neuro-cancer interactions: cellular phenotypes, spanning neurogliomal synapses, glioma networks, and neuronal-like motility; and transcriptional states, which exhibit remarkable resemblance to neural cells. These diverse cellular phenotypes and transcriptional states synergistically fuel glioma progression, invasion, and resistance. By emphasizing the converging phenotypical and transcriptional evidence with spatial context within them, an underexplored but critical role of neuro-cancer interactions are proposed in glioma intratumoral heterogeneity. This provides potential strategies to explore and disrupt these neuro-cancer interactions, offering new insights to address glioma intratumoral heterogeneity for improved therapeutic outcomes.

As the largest secondary lymphoid organ, the spleen plays a crucial role in initiating and sustaining immune responses against blood-borne pathogens through antigen capture and delivery. It is innervated by both autonomic and sensory nerves, which allows for neural modulation of its immune responses. The intricate spatial structure and precise coordination between immune and neural components are essential for proper splenic function, necessitating three-dimensional (3-D) imaging to reveal its architecture. However, the dense fibrous capsule and exceptionally rich vasculature of the spleen pose significant challenges for achieving comprehensive 3-D visualization of the entire organ. Here, we systematically evaluated and compared five cutting-edge tissue clearing approaches-ImmuView, fast light-microscopic analysis of antibody-stained whole organs, small-micelle-mediated human organ efficient clearing and labeling (SHANEL), advanced clear, unobstructed brain imaging cocktails and computational analysis (advanced CUBIC), and clearing-enhanced 3-D microscopy-for their effectiveness in rendering the spleen transparent for multiplexed antibody staining and high-resolution 3-D imaging. Our results indicated that SHANEL provided the clearest visualization of essential splenic neural and immune components. Meanwhile, advanced CUBIC achieved the greatest labeling efficacy for immune cells, albeit with slightly reduced transparency. Importantly, our study marked the first application of these optimized protocols to human spleen tissue, successfully revealing the highly organized immune cell zones and neural networks with enhanced clarity. Notably, we identified the nociceptive sensory innervation within human spleen tissue for the first time. Collectively, these findings establish optimal imaging strategies for visualizing splenic immune cells and neural structure in both murine and human tissues, providing profound insights into the intricate neuroimmune interactions and their pivotal roles in the immune functions of the spleen.NEW & NOTEWORTHY This study systematically assessed five tissue-clearing techniques and optimized the conditions of each protocol to overcome the challenges of splenic 3-D imaging posed by its dense structure and high pigmentation. The results demonstrated SHANEL and advanced CUBIC as the optimal methods for 3-D visualization of diverse splenic immune and neural architecture, with which we successfully mapped splenic neuroimmune landscape and identified nociceptive nerves within the human spleen for the first time.

Mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for ischemic stroke. However, the survival of transplanted MSCs is often compromised by the excessive levels of reactive oxygen species (ROS) and calcium ions (Ca2+) in the ischemic microenvironment following blood flow occlusion. In this study, a protective strategy is developed using functional nanomaterials to escort and shield MSCs. Specifically, NaGdF4@PDA-ALD nanoparticles (NPANs) are synthesized, featuring a NaGdF4 core coated with polydopamine (PDA) for ROS scavenging and further modified with alendronate sodium (ALD) for Ca2+ chelation. The internalization of NPANs by MSCs protected them from oxidative damage and calcium overload, thereby promoting their viability and functionality. Furthermore, NaGdF4 generated T1 signal enhancement, enabling in vivo tracking of MSCs via magnetic resonance imaging. The NPANs-treated MSCs demonstrated improved survival and migration to the ischemic region, promoting blood flow restoration and angiogenesis. These findings confirm the feasibility of employing functional nanoparticles to augment MSCs-based therapies, offering a promising strategy to improve their therapeutic efficacy in ischemic stroke treatment.

Lipid droplet (LD)-mediated organelle interactions promote tumor progression and immune evasion in tumors, but directly targeting LD remains challenging. Here, we developed a strategy to reverse LD function for hepatocellular carcinoma (HCC) immunotherapy. We first established a positive correlation between LD-related proteins and poor prognosis in HCC patients. We then engineered F127-modified, linoleic acid (LA)-capped copper MOF nanoparticles (LCMF NPs). These NPs are recognized by CD36 and internalized into LDs. Whereafter, copper ions catalyze surface LA into radicals via Fenton reaction, triggering a polyunsaturated fatty acid peroxidation cascade. This chemical reaction reverses the protective effect of LDs on organelles into an oxidative damage effect. Mechanistically, this process induces significant DNA damage, upregulating key immunogenic cell death markers HMGB1 and calreticulin. In vivo, reversing LD function reshapes the immunosuppressive tumor microenvironment and inhibits growth of both primary and distant tumors. Overall, this LD functional reversal strategy establishes LD-organelle networks as viable immunotherapy targets and offers a promising approach for treating metastatic tumors via organelle-level metabolic disruption.