International Journal Of Biological Sciences[JOURNAL]
Sun
200 papers
Deciphering the Neuroautophagic Interactome: Molecular Circuits Linking Selective Autophagy to Neuropathological Cascades in Neurological Disorders.
Luo P, Travis ZD, Lenahan C … +4 more , Wu H, Zhang J, Yu J, Xu W
Int J Biol Sci · 2026 · PMID 42328460 · Full text
Selective autophagy, a lysosome-dependent degradation pathway targeting specific substrates (e.g., mitochondria, protein aggregates), plays a pivotal role in maintaining neuronal homeostasis. Its dysregulation is intrica...
Selective autophagy, a lysosome-dependent degradation pathway targeting specific substrates (e.g., mitochondria, protein aggregates), plays a pivotal role in maintaining neuronal homeostasis. Its dysregulation is intricately linked to neurodegenerative diseases, acute brain injuries, and neuroinflammatory disorders. This review elucidates the crosstalk between selective autophagy and key neuropathophysiological processes, including apoptosis, neuroinflammation, oxidative stress, and blood-brain barrier disruption. We delineate the dual roles of selective autophagy through the framework of the neuroautophagic interactome-a network in which kinases (ULK1, TBK1) and effectors (PINK1/Parkin, SQSTM1/p62) collaboratively interpret ubiquitin codes. This integrated signaling nexus functions as a decisive hub that bidirectionally modulates disease progression. Furthermore, we evaluate emerging therapeutic strategies targeting selective autophagy to mitigate neuronal damage, emphasizing its dual role as both a protector and a contributor to disease progression.
Targeting THOC2-Mediated mRNA Export Induces PARP Inhibitor Vulnerability in DNA Repair-Competent Hepatocellular Carcinoma.
Li X, Yang S, Zhang M … +12 more , Guo Z, Wang Y, Meng Y, Liu Y, Zhang H, Xu K, Zhang X, Zhai Y, Jin J, He F, Tian C, Sun A
Int J Biol Sci · 2026 · PMID 42328459 · Full text
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality in tumors with DNA repair defects, their clin...
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality in tumors with DNA repair defects, their clinical utility in HCC is hindered by the low prevalence of canonical repair gene mutations and the enhancing DNA repair capacity. Through proteomic analysis of two independent cohorts (=260), we identified the THO complex component THOC2 as a master regulator of DNA damage response (DDR) via mRNA nuclear export control. Clinically, THOC2 overexpression predicted poor survival (HR=2.68-6.84, <0.001) and correlated with enhanced DDR gene expression. Mechanistically, THOC2 chaperones mRNA nuclear export of DDR effectors (MDC1, PRKDC, MSH6) and proliferation drivers (TOP2A), thereby establishing a dual pro-repair/pro-growth program. Targeting this vulnerability, THOC2 knockdown induced synthetic lethality with PARPi, reducing Olaparib IC50 by up to 61% and suppressing tumor growth by 76% (<0.001). Our study illuminates mRNA transport as a druggable DDR modulator and establishes THOC2 as both a prognostic biomarker and a therapeutic target to overcome PARPi resistance in HCC. This work pioneers a strategy to expand synthetic lethality beyond genetic defects by targeting post-transcriptional regulation.
Targeting IL-1α Sensitizes HNSCC to PDT by Reversing Hypoxia and NF-κB-Driven Oxidative Stress Resistance.
Li Z, Ji Y, Zhao X … +6 more , Ma H, Chen W, Zhou Z, Wang X, Shen L, Zheng L
Int J Biol Sci · 2026 · PMID 42328458 · Full text
Photodynamic therapy (PDT) provides non-invasive precision for superficial lesions but achieves suboptimal responses in hypoxic tumors such as head and neck squamous cell carcinoma (HNSCC). Spatially heterogeneous resist...
Photodynamic therapy (PDT) provides non-invasive precision for superficial lesions but achieves suboptimal responses in hypoxic tumors such as head and neck squamous cell carcinoma (HNSCC). Spatially heterogeneous resistance mechanisms pose a major translational constraint for extending PDT applicability. To overcome this limitation, actionable targets were mapped within tumor spatial heterogeneity, circumventing conventional nanomaterial-based hypoxia-reversal strategies with inherent design complexity and protracted translation timelines. Spatial transcriptomic profiling of HNSCC specimens revealed pronounced molecular gradients along hypoxic regions, pinpointing as the most significantly upregulated transcript in hypoxic niches, which directly correlates with adverse clinical outcomes. PDT further amplified IL-1α expression, establishing a self-reinforcing resistance loop. Functional analyses confirmed that hypoxic tumor-derived IL-1α activates the NF-κB pathway to confer resistance against PDT-induced oxidative stress. Critically, the selective IL-1R1 antagonist AF12198 disrupted this resistance axis, significantly enhancing PDT efficacy across cellular models and patient-derived organoids (PDOs). Pharmacological blockade of the IL-1α/IL-1R1/NF-κB axis represents a clinically actionable strategy against intrinsic PDT resistance. By leveraging spatial heterogeneity to identify IL-1α as a druggable target, this study provides robust preclinical support for repurposing clinical IL-1 inhibitors to enhance PDT efficacy.
Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.
Yangzom T, Chen A, Lundberg BC … +1 more , Liang KX
Int J Biol Sci · 2026 · PMID 42328457 · Full text
Astrocyte dysfunction plays a pivotal role in the pathogenesis of POLG-related mitochondrial diseases, yet the underlying mechanisms remain poorly understood. Here, we employed human iPSC-derived astrocytes, cortical org...
Astrocyte dysfunction plays a pivotal role in the pathogenesis of POLG-related mitochondrial diseases, yet the underlying mechanisms remain poorly understood. Here, we employed human iPSC-derived astrocytes, cortical organoids and astrocyte-neuron co-culture systems to model mutations and investigate astrocyte-mediated neurotoxicity. Single-cell transcriptomic profiling revealed a marked expansion of A1 neurotoxic astrocytes, depletion of A2 neuroprotective astrocytes, and reduction of neuronal populations in POLG organoids. A1 astrocytes exhibited transcriptional signatures of mitochondrial dysfunction, inflammatory signaling (TGF-β, JAK-STAT), impaired neuro-supportive functions, and activation of senescence, autophagy, and proteostasis stress pathways. Co-cultured dopaminergic neurons displayed impaired morphology and widespread transcriptional downregulation of mitotic, cytoskeletal, and synaptic genes, along with activation of inflammatory and ion transport pathways. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) attenuated astrocyte reactivity, reduced IL-6 and CXCL1 secretion, improved neuronal structure and synaptic marker expression, and increased mtDNA copy number and ATP production in POLG astrocytes. Our study identifies NAD⁺ augmentation as a promising strategy to mitigate astrocyte-driven pathology in mitochondrial encephalopathies.
Spatial and single-cell transcriptomics reveal a HIF-1α/NF-κB-driven hypoxia-induced senescence axis in BPH epithelium.
Li Z, Hu S, Liu Z … +7 more , Zhang M, Chen S, Yu W, Ding M, Fan Y, Li S, Jin J
Int J Biol Sci · 2026 · PMID 42328456 · Full text
Benign prostatic hyperplasia (BPH) is an age-related prostate disorder with incompletely defined mechanisms. We integrated laser capture microdissection RNA sequencing, public single-cell RNA sequencing, public spatial t...
Benign prostatic hyperplasia (BPH) is an age-related prostate disorder with incompletely defined mechanisms. We integrated laser capture microdissection RNA sequencing, public single-cell RNA sequencing, public spatial transcriptomics, human tissue validation, mouse-model analyses, and perturbation assays to characterize hypoxia-associated epithelial senescence in BPH. SA-β-gal-positive cells were predominantly epithelial. RNA sequencing of SA-β-gal-positive epithelial cells revealed enrichment of hypoxia/HIF-1, NF-κB, cell-cycle arrest, and senescence-associated programs, with increased , senescence-marker, and SASP-associated gene expression. Single-cell and spatial analyses showed coordinated activation of hypoxia-response, NF-κB-related, and senescence-associated programs in luminal epithelial cells or luminal-dominant spots. In 52 human BPH specimens, epithelial HIF-1α staining was modestly but significantly associated with p21, p27, and Rb. , 1% O₂ exposure or overexpression induced senescence-associated phenotypes in BPH-1 and RWPE-1 cells, whereas HIF-1α inhibition or knockdown attenuated these effects. NF-κB inhibition or knockdown partially reversed HIF-1α-associated senescence phenotypes. Conditioned media from hypoxia-treated epithelial cells promoted stromal-cell proliferation and SASP-associated cytokine secretion in a partly -dependent manner. In a testosterone propionate-induced BPH-like mouse model, HIF-1α or NF-κB inhibition attenuated prostatic hyperplasia, epithelial remodeling, and senescence-marker expression. These findings link hypoxia-associated HIF-1α/NF-κB signaling to epithelial senescence and epithelial-stromal crosstalk in BPH.
Sleep Deprivation Promotes Colorectal Cancer in Apc Mice Associated with Modulation of Gut Microbiota and Related Metabolites.
Chen J, Su R, Kuang Y … +4 more , Liu X, He Y, Chen J, Zhang C
Int J Biol Sci · 2026 · PMID 42328455 · Full text
Sleep deprivation (SD) has emerged as an important environmental factor associated with colorectal cancer (CRC); however, the underlying mechanisms, particularly those involving the gut microbiota-metabolite axis, remain...
Sleep deprivation (SD) has emerged as an important environmental factor associated with colorectal cancer (CRC); however, the underlying mechanisms, particularly those involving the gut microbiota-metabolite axis, remain poorly understood. In this study, Apc mice, a well-established CRC model, were subjected to SD using a modified multiple-platform method. Fecal samples were analyzed using 16S rRNA gene sequencing and untargeted metabolomics, and tumor burden, intestinal inflammation, and gut barrier integrity were assessed by hematoxylin and eosin staining, immunofluorescence, and Alcian blue-periodic acid-Schiff staining. Our results showed that SD significantly aggravated CRC progression, as evidenced by an increase in tumor number and severity, impaired intestinal barrier integrity, and enhanced intestinal inflammation. In parallel, SD markedly altered the gut microbiota composition, characterized by a pronounced reduction in beneficial bacteria such as Lactobacillus. Metabolomic profiling revealed significant metabolic alterations, with taurocholic acid (TCA) identified as a prominently elevated metabolite. Transcriptomic and functional analyses suggested that TCA may be involved in CRC progression through the activation of the MAPK/ERK signaling pathway. Collectively, these findings support a model in which SD contributes to CRC progression in association with alterations in the gut microbiota and related metabolites.
Dual inhibition of PRMT1 and SUV39H1 suppresses breast cancer progression and enhances immunotherapy response.
Wang G, Song J, Duan X … +4 more , Zhou K, Zhang J, Zhang H, Yu Y
Int J Biol Sci · 2026 · PMID 42328454 · Full text
Protein arginine methyltransferase 1 (PRMT1) dysregulation is frequently observed in various human cancers, including breast cancer. However, the antitumor efficacy of PRMT1 inhibitors remains limited in the treatment of...
Protein arginine methyltransferase 1 (PRMT1) dysregulation is frequently observed in various human cancers, including breast cancer. However, the antitumor efficacy of PRMT1 inhibitors remains limited in the treatment of breast cancer. Here, we propose a dual epigenetic inhibition strategy that effectively suppresses breast cancer growth and metastasis. We demonstrate that GSK3368715, a small-molecule inhibitor of PRMT1, downregulates the protein levels of the histone lysine methyltransferase SUV39H1 by enhancing its ubiquitination. Dual inhibition of PRMT1 and SUV39H1 results in significantly greater suppression of tumor growth and metastasis compared to either monotherapy, supporting the synergistic effects of targeting two epigenetic regulators. Consistently, dual inhibition markedly suppresses the growth of breast cancer organoids relative to single-agent treatments. Mechanistically, co-inhibition of SUV39H1 and PRMT1 enhances chromatin accessibility in promoter regions, thereby promoting the expression of key regulators involved in cell growth and migration. Furthermore, dual inhibition increases infiltration of CD8 T cells and NK cells and upregulates PD-L1 expression. Importantly, the combination of dual inhibition with anti-PD-L1 antibody enhances the responsiveness of breast cancer to immunotherapy. Taken together, our findings indicate that co-targeting PRMT1 and SUV39H1 represents a promising therapeutic strategy for breast cancer.
Cholesterol Overload Drives Hepatic Steatosis by Inhibiting OGT-dependent PPARα O-GlcNAcylation and Transactivation.
Guo R, Li Y, Ding Q … +6 more , Slawson C, Apte U, Jiang Y, Dou X, Li S, Song Z
Int J Biol Sci · 2026 · PMID 42328453 · Full text
Although dietary cholesterol is known to exacerbate liver disease progression, whether and how it contributes to hepatic steatosis, the hallmark early pathological feature of both MASLD and ALD, remains poorly understood...
Although dietary cholesterol is known to exacerbate liver disease progression, whether and how it contributes to hepatic steatosis, the hallmark early pathological feature of both MASLD and ALD, remains poorly understood. Here, we investigated how cholesterol disrupts hepatic triacylglycerol metabolism using both dietary and cellular cholesterol-loading models. Integrated transcriptomic, metabolomic, and biochemical analyses were performed, and causality was examined through genetic and pharmacologic modulation in multiple hepatocyte systems and mice. Our results demonstrate that cholesterol overload induces hepatocellular fat accumulation in a dose-dependent, cell-autonomous manner, primarily by suppressing fatty acid β-oxidation. Mechanistically, we identified PPARα inhibition as a key event underlying this effect. Cholesterol overload suppressed PPARα transactivation, thereby impairing fatty acid β-oxidation and promoting hepatocellular fat accumulation. This inhibition was mechanistically linked to reduced O-GlcNAcylation. Specifically, cholesterol overload downregulated OGT, leading to reduced protein O-GlcNAcylation and consequent PPARα inhibition; similarly, liver-specific OGT knockout mice exhibited suppressed PPARα activity and increased hepatic fat accumulation. RNA-sequencing and co-immunoprecipitation analyses identified PPARα as an O-GlcNAc-modified protein, and loss of this modification impaired its transactivity. Functionally, restoration of O-GlcNAcylation via genetic OGA knockdown or pharmacological activation of PPARα with WY14643 alleviated cholesterol-induced hepatic steatosis in mice without altering hepatic cholesterol levels. Lastly, we identified SREBP2 as the upstream transcriptional regulator linking cholesterol overload to OGT suppression. In conclusion, our findings in this study uncover a previously unrecognized cholesterol-OGT-PPARα axis that suppresses hepatic fatty acid β-oxidation and drives steatosis. Targeting O-GlcNAc cycling or activating PPARα represents a promising therapeutic strategy for MASLD.
Cancer-associated adipocytes confer CDK4/6 inhibitor resistance in ER+ breast cancer through an IL-6/STAT3/SREBF2 axis coupled with cholesterol metabolism and cell cycle reprogramming.
Huang R, Tong Y, Sun X … +5 more , Wang H, Wang Z, Tang Y, Shen K, Chen X
Int J Biol Sci · 2026 · PMID 42328452 · Full text
Cancer-associated adipocytes (CAAs) within the tumor microenvironment (TME) critically regulate oncogenic progression. However, the mechanistic basis underlying CAAs-mediated CDK4/6 inhibitor (CDK4/6i) resistance in estr...
Cancer-associated adipocytes (CAAs) within the tumor microenvironment (TME) critically regulate oncogenic progression. However, the mechanistic basis underlying CAAs-mediated CDK4/6 inhibitor (CDK4/6i) resistance in estrogen receptor-positive (ER+) breast cancer remains elusive. In this study, we revealed that CAAs supernatant demonstrated enhanced capacity to induce CDK4/6i resistance in ER+ breast cancer cells compared to NAs-derived conditioned medium. Through integrated RNA sequencing and cytokine microarray screening, we identified marked upregulation of IL-6 in both CAAs and their conditioned media. Mechanistically, CAAs-derived IL-6 activates the JAK-STAT3 axis, leading to transcriptional upregulation of SREBF2, which directly drives CDK4/6i resistance through HMGCR-mediated lipid metabolism and CDKN2C-mediated cell cycle progression (IL-6STAT3SREBF2-HMGCR/CDKN2C axis). Reciprocally, breast cancer cell-secreted exosomal miR-1246 promotes the transformation of normal adipocytes (NAs) to CAAs via PAX5-dependent regulation, and CAAs highly express UCHL1, which stabilizes KLF5 through K48-linked deubiquitination to activate NF-κB signaling, thereby augmenting IL-6 production (exosomal miR-1246-PAX5 and UCHL1-KLF5-NF-κB loop). Pharmacologic inhibition of HMGCR with simvastatin, alone or combined with IL-6 blockade, restored CDK4/6i sensitivity in vitro and in vivo, highlighting a clinically accessible strategy to overcome adipocyte-mediated resistance. Collectively, our findings establish that CAAs confer CDK4/6i resistance in ER+ breast cancer through the IL-6-driven SREBF2 activation axis, sustained by a reciprocal exosomal miR-1246/UCHL1-mediated feedback loop.
Targeting SRSF6 to Enhance Cisplatin Sensitivity by Modulating Redox Balance via NFE2L1 exon 4 Splicing in ESCC.
He X, Xu J, Duan L … +12 more , Ma J, Gao D, Xie Y, Zhao D, Liu J, Zhao J, Liu F, Lee MH, Kim MO, Dong Z, Jiang Y, Liu K
Int J Biol Sci · 2026 · PMID 42328451 · Full text
The mechanisms by which cancer cells survive and adapt under high levels of reactive oxygen species (ROS) remain poorly understood, especially in the context of redox homeostasis. This study reveals increased oxidative s...
The mechanisms by which cancer cells survive and adapt under high levels of reactive oxygen species (ROS) remain poorly understood, especially in the context of redox homeostasis. This study reveals increased oxidative stress in esophageal squamous cell carcinoma (ESCC), with serine/arginine-rich splicing factor 6 (SRSF6) playing a crucial role in maintaining redox homeostasis. SRSF6 binds to the exonic splicing enhancer (ESE) motif in nuclear factor erythroid 2-related factor 1 (NFE2L1 Exon 4, preventing exon skipping and promoting the production of specific isoforms that promote ESCC cell proliferation. This interaction enhances cellular antioxidant capacity, thereby influencing redox balance. Moreover, reducing SRSF6 increases the levels of NFE2L1-S, the isoform produced by exon 4 skipping in the gene, which elevates ROS levels and induces apoptosis and ferroptosis. Notably, SRSF6 and NFE2L1 form a positive feedback loop: NFE2L1 serves as the transcription factor for SRSF6, while SRSF6 acts as the splicing factor for NFE2L1. Antisense oligonucleotides (ASOs) targeting SRSF6 significantly suppress ESCC cell growth. Importantly, inhibiting this feedback loop also enhances cisplatin (CDDP) sensitivity, increasing the therapeutic efficacy of CDDP. Our findings highlight the critical role of the SRSF6-NFE2L1 axis in redox homeostasis and tumor progression, positioning SRSF6 as a distinctive therapeutic target to improve treatment outcomes in ESCC.
USP18 Impacts Cisplatin Resistance in Ovarian Cancer Cells by Modulating DNA Repair.
Corno C, Costantino M, Pettinari P … +21 more , Mirra L, Stucchi S, Arrighetti N, Perta N, Di Muccio G, Robin M, Beretta GL, Corna E, Carenini N, Cleris L, Colombo D, Luison E, Ciniselli CM, Lecchi M, Verderio P, Figini M, Linder S, Tosi D, La Teana A, D'Arcy P, Perego P
Int J Biol Sci · 2026 · PMID 42328450 · Full text
Deubiquitinases (DUBs) are proteases with emerging roles in cancer, yet their contribution to drug resistance in ovarian cancer remains underexplored. Ovarian cancer patients often fail to benefit from platinum-based the...
Deubiquitinases (DUBs) are proteases with emerging roles in cancer, yet their contribution to drug resistance in ovarian cancer remains underexplored. Ovarian cancer patients often fail to benefit from platinum-based therapy, highlighting the need to identify novel factors driving drug resistance. Thus, we performed a CRISPR/Cas9 screen targeting the DUB family to identify genes essential for cisplatin-resistant ovarian carcinoma cell survival. CRISPR/Cas9 DUB knockout screens, preclinical pharmacology approaches, RNA sequencing, proteomic analyses, computational tools, surface plasma resonance were applied. We identified USP18 as a survival factor in cisplatin-resistant ovarian cancer cells. USP18 expression was elevated at the mRNA and protein levels across five cisplatin-resistant variants. Knockdown and CRISPR/Cas9 editing of USP18 sensitized cells to cisplatin, coinciding with impaired repair of cisplatin-induced DNA damage. Enhanced sensitivity to cisplatin was evident from studies in mice. RNA-seq of USP18 RNA interfered and edited cells revealed the modulation of pathways including DNA repair. A peptide-based USP18 inhibitor suppressed growth of cisplatin-resistant cells, supporting USP18 role in sustaining their growth. We identified USP18 as a novel mediator of cisplatin resistance in ovarian cancer, acting through DNA repair modulation. Targeting USP18 may offer a therapeutic strategy to improve outcomes in platinum-resistant ovarian cancer.
Copper-Iron Cell Death Axis: Mechanistic Crosstalk, Disease Implications and an Integrated Metallo-Redox-Metabolic Framework.
Huang H, Chen Y, Lu Y … +8 more , Yuan Z, Zahoor A, Ren L, Luo Y, Zhong B, Huang J, Chen H, Ning L
Int J Biol Sci · 2026 · PMID 42328449 · Full text
Cuproptosis and ferroptosis are two major forms of metal-dependent cell death, characterized by mitochondrial proteotoxicity and lipid peroxidation, respectively, and are broadly implicated in diverse disease contexts. H...
Cuproptosis and ferroptosis are two major forms of metal-dependent cell death, characterized by mitochondrial proteotoxicity and lipid peroxidation, respectively, and are broadly implicated in diverse disease contexts. Here, by integrating mechanistic, biological, and disease-associated evidence, we propose the metal-metabolism-redox vulnerability axis, which describes cellular states under metal stress as a continuous space defined by metal homeostasis, mitochondrial metabolism, and redox balance. Within this space, cuproptosis and ferroptosis correspond to distinct execution regions rather than independent processes. Building on this concept, we further establish a metallo-redox-metabolic framework to explain how key state variables and their coupling relationships determine execution bias and drive dynamic transitions between death modalities. This framework reframes metal-dependent cell death as a state-driven system rather than a collection of discrete pathways and provides a unified perspective for understanding its roles in complex diseases. In addition, we outline predictive and testable hypotheses and highlight the importance of multi-omics integration and artificial intelligence based modeling in capturing cellular state and enabling dynamic prediction. Collectively, this work provides a conceptual foundation for understanding metal-driven cell fate decisions and for developing state-oriented therapeutic strategies.
Slc1a2-mediated Glutamate Transport Promotes Dendritic Cell Immunity through Sema3A-regulated Cytoskeletal Remodeling and Migration.
Chen S, Chen B, Li G … +6 more , Liu H, Chen Q, Chen J, Xu Y, Aipire A, Li J
Int J Biol Sci · 2026 · PMID 42328448 · Full text
Dendritic cells (DCs) can activate T cells to trigger sustained antitumor immune responses, a process in which the continuous migration of antigen-loaded DCs from the tumor microenvironment to tumor-draining lymph nodes...
Dendritic cells (DCs) can activate T cells to trigger sustained antitumor immune responses, a process in which the continuous migration of antigen-loaded DCs from the tumor microenvironment to tumor-draining lymph nodes is critical. DCs have evolved a complex and dynamic regulatory network to mediate their migration to specific locations, with multiple transporters including amino acid transporters reported to participate in this process. Slc1a2 is highly expressed in the nervous system, where it mediates the clearance of extracellular glutamate, primarily in astrocytes; however, its role in the immune system remains unclear. In this study, we showed that activated DCs upregulated Slc1a2 to boost glutamate uptake, which in turn promoted DC functionality and antitumor vaccine potency. Furthermore, glutamate signaling induced Sema3A, which elevated small GTPase signaling pathways (e.g., RhoA/Rac1/Cdc42) and drove dynamic cytoskeletal remodeling, thereby providing the necessary molecular machinery for DC migration during antitumor immunity . We first demonstrated that Slc1a2-mediated glutamate metabolism functioned as a metabolic checkpoint for DC migration and antigen-specific immunity , with the Sema3A/small GTPase axis serving as the core mechanism linking glutamate signaling to cytoskeletal reorganization.
Macrophage-Orchestrated Metabolic Sensing Drives IBD Pathogenesis: A Framework for Targeted Therapy.
Guan G, Sun X, Chen Y … +2 more , Guo Q, Dong Y
Int J Biol Sci · 2026 · PMID 42328447 · Full text
Inflammatory bowel disease (IBD) arises from dysregulated interactions among the gut microbiota, immune system, and intestinal epithelium. Intestinal macrophages are central to these processes, yet are often viewed prima...
Inflammatory bowel disease (IBD) arises from dysregulated interactions among the gut microbiota, immune system, and intestinal epithelium. Intestinal macrophages are central to these processes, yet are often viewed primarily as downstream inflammatory effectors. Here, we present a conceptual review that reframes intestinal macrophages as metabolic sensors and regulatory hubs that orchestrate inflammatory persistence or resolution. We propose a Macrophage-Orchestrated Metabolic Sensor (MOMS) framework organized into three coordinated layers: Sense, in which macrophages detect microbial- and host-derived metabolites; Switch, in which metabolic and epigenetic reprogramming stabilizes intracellular inflammatory or reparative states; and Command, in which these stabilized states drive epithelial repair, immune-cell recruitment, or fibrotic remodeling. Integrating evidence from immunometabolism, microbiome research, and single-cell biology, we identify key molecular nodes-including METTL3 and NLRP3-as programmable regulators of macrophage fate. The MOMS framework generates testable predictions linking macrophage metabolic states to disease severity and treatment responsiveness, and provides a conceptual foundation for precision macrophage-directed therapies in IBD and related immune-metabolic disorders.
RMAD1, a Novel Cell-Penetrating Peptide Derived from ADARB2: Preclinical Insights into Antigen Uptake and T Cell Activation.
Lim C, Park C, Song EC … +7 more , Shin Y, Kim WK, Park YJ, Youn H, Ham C, Kim SB, Cho S
Int J Biol Sci · 2026 · PMID 42328446 · Full text
The development of effective cancer vaccines remains a major challenge in oncology, largely due to limited antigen delivery and suboptimal T cell priming. Here, we report RMAD1, a novel human-derived cell-penetrating pep...
The development of effective cancer vaccines remains a major challenge in oncology, largely due to limited antigen delivery and suboptimal T cell priming. Here, we report RMAD1, a novel human-derived cell-penetrating peptide (CPP) originating from the ADARB2 (Adenosine Deaminase RNA Specific B2) protein, identified through an intra-dermal delivery technology (IDDT) platform, and evaluate its potential as a vaccine delivery enhancer. RMAD1 exhibited superior intracellular delivery compared with conventional CPPs and preferential uptake by antigen-presenting cells (APCs), including dendritic cells and macrophages. RMAD1 conjugated vaccines showed enhanced accumulation in draining lymph nodes and facilitated efficient antigen cross-presentation through the MHC class I pathway. In murine E.G7-OVA and TC-1 tumor models, RMAD1 conjugated vaccines induced robust antigen-specific CD8⁺ T cell responses across peripheral blood, lymphoid organs, and tumor tissues. Functional analyses revealed increased IFN-γ and TNF-α production by both CD8⁺ and CD4⁺ T cells, accompanied by a reduction in Foxp3⁺CD25⁺ regulatory T cells. In addition, RMAD1 conjugation promoted epitope spreading and established durable immunological memory, resulting in protection against tumor rechallenge. Therapeutic efficacy was further demonstrated in a TC-1 lung metastasis model, where RMAD1-based vaccination significantly reduced metastatic burden. Importantly, RMAD1-vaccinated mice exhibited therapeutic efficacy comparable to cisplatin treatment, while demonstrating a favorable safety profile. Together, these findings position RMAD1 as a next-generation CPP platform that outperforms existing peptides in enhancing antigen delivery and anti-tumor immunity, offering a promising strategy for advancing cancer vaccine development.
Reimagining AHR in Cancer: From Environmental Sensor to Novel Immunomodulatory Therapeutic Target.
Peng Y, Zhao Y, Zhou Y … +3 more , Liu S, Xiao D, Tao Y
Int J Biol Sci · 2026 · PMID 42328445 · Full text
The aryl hydrocarbon receptor (AHR) is an environmental sensor in mammals and a ligand-dependent, highly conserved transcription factor. It belongs to the basic helix-loop-helix family of transcription factors and is the...
The aryl hydrocarbon receptor (AHR) is an environmental sensor in mammals and a ligand-dependent, highly conserved transcription factor. It belongs to the basic helix-loop-helix family of transcription factors and is the only known ligand-activated member within this family. Previous studies have revealed its significant roles in physiological regulation, metabolic homeostasis, and tumorigenesis. governs transcriptional regulation and epigenetic modifications through diverse mechanisms and plays an important role in various types of cancer. In this review, we introduce the history and structure of and summarize its modes of action via canonical and non-canonical pathways. We elaborate on the distinct impact of on mitochondrial metabolism, epigenetics, as well as cell death and fate. Furthermore, we systematically discuss the relationship between and tumor immunity. Finally, we explore the prospects of in the tumor microenvironment, cancer immunity and therapy, and its potential as an immunotherapeutic target, along with current achievements in drug development targeting AHR. These research findings may provide insights into the relationship between AHR and its regulated molecules and pathways in cancer, as well as mechanisms for cancer treatment and intervention.
Targeting the exosomal CaMK2A-ZDHHC3-GPX4 pathway reprograms tumor-associated macrophages and enhances anti-PD-1/PD-L1 immunotherapy in gastric cancer.
Chen Z, Huang H, Shen Y … +6 more , Yamamoto M, Tsukamoto T, Nomura S, Jiang T, Xu Z, Li Z
Int J Biol Sci · 2026 · PMID 42328444 · Full text
BACKGROUND: Gastric cancer (GC) remains a major global health challenge, characterized by poor outcomes driven by an immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), particularly the M...
BACKGROUND: Gastric cancer (GC) remains a major global health challenge, characterized by poor outcomes driven by an immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), particularly the M2 subtype, are central mediators of immune evasion and therapeutic resistance. While tumor-derived exosomes are key regulators of intercellular communication, the mechanisms by which they modulate TAM fate remain unclear. METHODS: Proteomic profiling, molecular assays, and models were used to identify GC-derived exosomal cargos regulating macrophage polarization. The CaMK2A-ZDHHC3-GPX4 axis was dissected using phosphorylation, palmitoylation, and genetic perturbation analyses. The therapeutic implications were evaluated through macrophage-specific GPX4 ablation and anti-PD-1/PD-L1 blockade in murine GC models. RESULTS: We identified exosomal CaMK2A as a critical determinant of TAM polarization. Internalized CaMK2A phosphorylates ZDHHC3 at Thr176, enhancing GPX4 S-palmitoylation at Cys10, preventing its lysosomal degradation, and stabilizing GPX4 protein. This cascade suppresses macrophage ferroptosis and promotes M2 polarization, fostering tumor proliferation and metastasis. Conversely, GPX4 deletion in macrophages restrains tumor growth and synergizes with PD-1/PD-L1 blockade to enhance antitumor immunity. Clinically, GPX4 is upregulated in GC, enriched in TAMs, and predicts poor prognosis. CONCLUSIONS: Our study reveals a previously unrecognized CaMK2A-ZDHHC3-GPX4 signaling axis that couples ferroptosis resistance to immunosuppressive TAM polarization. Targeting GPX4 or disrupting exosomal CaMK2A signaling may reprogram the TME and potentiate immune checkpoint therapy in GC.
PFKFB3 Mediated Glycolytic Reprogramming Drives Vascular Endothelial Injury Under Chronic Intermittent Hypoxia.
Li SQ, Wang Y, Zhang L … +8 more , Yan YR, Lu FY, Chen XX, Lin YN, Lin JQ, Zhou JP, Lu LM, Li QY
Int J Biol Sci · 2026 · PMID 42328443 · Full text
Metabolic-inflammatory crosstalk is a hallmark of cardiovascular pathogenesis. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for cardiovascular diseases...
Metabolic-inflammatory crosstalk is a hallmark of cardiovascular pathogenesis. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for cardiovascular diseases. While endothelial inflammation driven by CIH is pivotal in disease progression, the underlying metabolic mechanisms remain poorly defined. Our research shows that phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic activator, is markedly upregulated in endothelial cells (ECs) exposed to CIH, correlating with enhanced glycolysis, suppressed mitochondrial respiration, and amplified inflammatory responses. Endothelial-specific PFKFB3 deficiency or pharmacological suppression of PFKFB3 restores the glycolytic balance and alleviates vascular endothelial injury. Mechanistically, CIH enhances the expression of hypoxia-inducible factor 1α (HIF-1α), which regulates PFKFB3 expression. PFKFB3-induced production of lactate further promotes H3K18 lactylation (H3K18la), which in turn binds the PFKFB3 promoter, forming a positive-feedback loop. Disruption of the HIF-1α/PFKFB3 axis alleviates the inflammatory and glycolytic signatures of ECs. In conclusion, our findings identify PFKFB3 as a critical metabolic driver of endothelial inflammation under CIH, orchestrated through a HIF-1α-PFKFB3-H3K18la loop. These findings reveal novel pathogenic insights and potential therapeutic targets for OSA-associated cardiovascular diseases.
The TRPM7 inhibitor carvacrol suppresses angiogenesis and vasculogenic mimicry in triple-negative breast cancer.
Tang T, Zhao N, Qiu M … +7 more , Müller L, Menger MD, Chubanov V, Gudermann T, Krasteva-Christ G, Laschke MW, Gu Y
Int J Biol Sci · 2026 · PMID 42328442 · Full text
Vasculogenic mimicry (VM) contributes significantly to tumor aggressiveness and resistance to anti-angiogenic therapies. Simultaneous inhibition of both angiogenesis and VM represents a promising strategy to improve ther...
Vasculogenic mimicry (VM) contributes significantly to tumor aggressiveness and resistance to anti-angiogenic therapies. Simultaneous inhibition of both angiogenesis and VM represents a promising strategy to improve therapeutic outcomes in aggressive cancers, such as triple-negative breast cancer (TNBC), which responds poorly to anti-angiogenic therapies. In this study, we identified carvacrol, a natural monoterpenoid phenol widely used as a food additive, as a dual inhibitor of angiogenesis and VM in TNBC. Carvacrol preferentially inhibited angiogenesis in endothelial cells (ECs) and VM in TNBC cells at concentrations that had minimal effects on TNBC cell proliferation. Mechanistically, carvacrol directly bound to the vanilloid-like (VL) site of transient receptor potential melastatin 7 (TRPM7), thereby inhibiting channel activity and attenuating Zn influx. This triggered dephosphorylation of the mammalian target of rapamycin (mTOR) and subsequent proteasomal and lysosomal degradation of key receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR2), Tie2, fibroblast growth factor receptor 1 (FGFR1), and insulin-like growth factor 1 receptor (IGF1R) in ECs, as well as FGFR1 and IGF1R in TNBC cells. Genetic knockdown of TRPM7 recapitulated the anti-vascular effects and signaling alterations induced by carvacrol. , carvacrol effectively suppressed TNBC vascularization and growth in a mouse dorsal skinfold chamber model and an orthotopic xenograft model. Together, these findings suggest that carvacrol preferentially targets angiogenesis and VM in TNBC by suppressing the TRPM7/Zn/mTOR/RTKs axis, highlighting it as a promising therapeutic candidate for TNBC and potentially other tumors resistant to anti-angiogenic therapies, while positioning the TRPM7 channel as a novel anti-vascular target for TNBC treatment.
Comprehensive Metabolomic Profiling of Skin Lesions from Psoriasis Patients Reveals Disease Signatures.
Zhu P, Wang Y, Sun J … +9 more , Cai J, Chen Z, Cui L, Song X, Wang Y, Yu Z, Gong Y, Yu Q, Shi Y
Int J Biol Sci · 2026 · PMID 42328441 · Full text
Psoriasis is a chronic skin disease caused by dysregulated immune system. Although inflammation plays a vital role, the precise chemical changes within the skin remain unclear and metabolomic profiling of skin lesions ha...
Psoriasis is a chronic skin disease caused by dysregulated immune system. Although inflammation plays a vital role, the precise chemical changes within the skin remain unclear and metabolomic profiling of skin lesions has been limited by small sample sizes and narrow metabolite coverage. In this study, we performed wide-targeted metabolomics of skin samples from 30 psoriasis patients and 30 healthy controls to identify differential metabolites that may drive the disease. We identified 707 differential metabolites across 21 classes, including amino acids, fatty acids, organic acids, nucleotides, and others. Among them, two metabolites, UDP-N-acetyl-3-O-(1-carboxyvinyl)-D-glucosamine and ethylparaben, were strongly linked to psoriasis. Further analysis revealed that these changes were driven by specific differentiated keratinocytes and involved metabolomic enzyme-encoding genes related to nucleotide and pyrimidine metabolism pathways. To identify metabolites associated with disease severity, we grouped patients by PASI and BSA scores and identified 27 metabolites that increased as the disease worsened via Mfuzz clustering analysis. Among them, citrate and L-tyrosine significantly exacerbated disease by increasing skin thickness and inflammation after validation in vivo. Our findings provide a comprehensive map of metabolic changes in psoriatic skin and highlight citrate and L-tyrosine as potential indicators for disease severity and promising targets for future treatments.
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