International Journal Of Biological Sciences[JOURNAL]
Sun
200 papers
Pancreatic cancer-associated myofibroblasts: a review.
Banacki M, Inkielewicz-Stepniak I
Int J Biol Sci · 2026 · PMID 41943847 · Full text
Pancreatic cancer is a very deadly disease, with no effective therapy currently employed in clinical practice, highlighting the urgent need for new therapeutic strategies. Cancer cells represent a minority within the pan...
Pancreatic cancer is a very deadly disease, with no effective therapy currently employed in clinical practice, highlighting the urgent need for new therapeutic strategies. Cancer cells represent a minority within the pancreatic tumor, which is characterized by a pronounced stromal compartment. As fibrosis is characteristic of pancreatic ductal adenocarcinoma, the cell population of particular interest is the pancreatic cancer-associated myofibroblast population, observed to be the main extracellular matrix producers. Recent studies revealed a plurality of myofibroblast functions in the pancreatic tumor, beyond their role in matrix secretion: they were noted to promote cancer cell proliferation and invasiveness in and studies, and have been described as potential prognostic biomarkers, along with stromal collagen content. Moreover, myofibroblasts were found in precancerous pancreatic lesions, and may thus be involved in pancreatic carcinogenesis. Paradoxically, depletion of myofibroblasts had detrimental effects on the outcome in an study, and their precise role in the disease remains unclear. This review summarizes for the first time studies on pancreatic cancer-associated myofibroblasts, focusing on the origin, function, biomarker potential, and heterogeneity of these cells in the pancreatic tumor, aiming to elucidate their role in pancreatic cancer progression.
Synergistic Neurotoxicity of environmental Cadmium and Paraquat in Parkinsonism: Unveiling the Mito-ROS/OPA1/Caspase-3/GSDME-driven Apoptosis Axis.
Luo Y, Lu Y, Tang Y … +13 more , Zhao X, Wang J, Liu Y, Jiang S, Zhu Y, Qi J, Xing L, Yan C, Liu X, Huang C, Wang H, Xu H, Wang L
Int J Biol Sci · 2026 · PMID 41943846 · Full text
The increasing environmental presence of cadmium (Cd) and paraquat (PQ), driven by industrial emissions and overuse of herbicide, poses heightened risks for neurodegenerative disorders. Although each of these toxins can...
The increasing environmental presence of cadmium (Cd) and paraquat (PQ), driven by industrial emissions and overuse of herbicide, poses heightened risks for neurodegenerative disorders. Although each of these toxins can independently induce neuronal damage, the synergistic neurotoxic effects resulting from chronic, low-dose co-exposure to Cd and PQ remain inadequately understood. This study demonstrates that exposure to subtoxic levels of Cd and PQ concurrently induces neuronal cell death and contributes to Parkinson's disease (PD)-like symptoms. Mechanistically, chronic co-exposure to Cd and PQ triggers a marked overproduction of mitochondrial ROS (mito-ROS), which impairs OPA1 processing and results in mitochondrial fragmentation. This mitochondrial dysfunction subsequently triggers caspase-3 activation, leading to GSDME cleavage and its translocation to the mitochondria, ultimately promoting neuronal apoptosis. Furthermore, our studies demonstrate significant mitochondrial dysfunction and loss of nigrostriatal dopaminergic neurons, resulting in motor deficits and cognitive impairments in mice co-exposed to these toxins. Collectively, our findings reveal a novel molecular mechanism involving the mito-ROS/OPA1/caspase-3/GSDME pathway in environmentally-induced PD-like pathology, thereby offering potential therapeutic insights for PD treatment.
Role of Copper Homeostasis and Cuproptosis in Cardiovascular Disease: Molecular Insights and Metabolic Perspectives.
Yu X, Yuan D, Wang Y … +4 more , Wang L, Zhu L, An Q, Ling Y
Int J Biol Sci · 2026 · PMID 41943845 · Full text
Copper is an essential trace element; however, its homeostasis is frequently disrupted in cardiovascular diseases, which are a leading cause of mortality worldwide. The recent discovery of cuproptosis-a copper-dependent...
Copper is an essential trace element; however, its homeostasis is frequently disrupted in cardiovascular diseases, which are a leading cause of mortality worldwide. The recent discovery of cuproptosis-a copper-dependent form of regulated cell death (RCD)-has provided a crucial mechanistic link between this imbalance and cardiomyocyte loss. In this review, we synthesize the current understanding of how dysregulated copper metabolism and cuproptosis drive the pathogenesis of major cardiovascular conditions, including myocardial ischemia/reperfusion (I/R) injury, anthracycline-induced cardiotoxicity, atherosclerosis, diabetic cardiomyopathy (DCM), and sepsis-induced cardiac dysfunction, through pathways such as mitochondrial dysfunction, oxidative stress, and inflammation. We further evaluated emerging therapeutic strategies that target copper homeostasis-including chelators, chaperone inhibitors, and ionophores-and critically analyzed the translational challenges they face, such as off-target effects and preclinical model limitations. Advancing our knowledge of cardiac copper biology holds significant promise for the development of novel and precise therapeutic approaches for cardiovascular diseases.
IGF2BP2 Deficiency in Macrophages Impairs Migration, Reprograms Metabolism, and Limits Tumor Progression.
Schymik HS, Wrublewsky S, Höring M … +12 more , Liebisch G, Both S, Gasparoni G, Bickelmann C, Robertson H, Dahlem C, Walter J, Helms V, Laschke MW, Ampofo E, Hoppstädter J, Kiemer AK
Int J Biol Sci · 2026 · PMID 41943844 · Full text
While insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been extensively studied in tumor cells, its role in immune cells within the tumor microenvironment, particularly in macrophages, remains largely un...
While insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been extensively studied in tumor cells, its role in immune cells within the tumor microenvironment, particularly in macrophages, remains largely unknown. Here, we reveal a critical function of IGF2BP2 in macrophages, demonstrating that myeloid-specific deletion of IGF2BP2 profoundly alters macrophage metabolism and polarization, and markedly impairs tumor progression. Bulk RNA sequencing of IGF2BP2 knockout (KO) macrophages revealed significant alterations in gene expression profiles, particularly impacting pathways associated with glycolysis, mitochondrial function, cell motility, and cell migration. Functional assays confirmed increased glycolytic activity and a concomitant reduction in maximal respiration and reserve respiratory capacity, indicating a metabolic shift towards glycolysis. Furthermore, IGF2BP2 deficiency impaired tumor-associated macrophage (TAM)-like polarization , as evidenced by decreased expression of TAM markers, such as , , and . Lipidomic profiling revealed distinct lipid signatures in IGF2BP2 KO TAM-like macrophages, including alterations in triglycerides and cardiolipins, crucial for mitochondrial integrity. , deletion of IGF2BP2 specifically in the myeloid lineage was sufficient to reduce tumor growth in a subcutaneous Lewis lung carcinoma model, accompanied by decreased TAM infiltration and a shift towards a pro-inflammatory macrophage phenotype. Additionally, IGF2BP2-deficient macrophages showed impaired migratory capacity both and . These findings underscore the critical role of IGF2BP2 in controlling macrophage metabolism, polarization, and tumor-supporting functions within the tumor microenvironment, and identify myeloid IGF2BP2 as a potential therapeutic target in cancer.
Orchestrating Tumor Metastasis: Exosomes as Master Regulators of the Local and Distant Microenvironment.
Zhao Y, Liu A, Zhang X … +2 more , Zeng A, Song L
Int J Biol Sci · 2026 · PMID 41943843 · Full text
Metastasis remains a critical challenge in oncology and constitutes the leading cause of cancer mortality. Recent studies have revealed that exosomes are involved in every step of the cascades of tumor invasion and metas...
Metastasis remains a critical challenge in oncology and constitutes the leading cause of cancer mortality. Recent studies have revealed that exosomes are involved in every step of the cascades of tumor invasion and metastasis. Therefore, it is necessary to further investigate the exosome-mediated intercellular communication network within the tumor microenvironment to elucidate the mechanisms of cancer metastasis. This review summarizes alterations in the tumor microenvironment at primary and metastatic sites during metastasis, encompassing processes such as epithelial-mesenchymal transition (EMT) induction, extracellular matrix (ECM) remodeling, immune suppression, and angiogenesis. In addition, we examine the role of exosomes in mediating tumor drug resistance and explore the clinical translational potential of exosomes in biomarker detection, drug delivery systems, and cancer vaccines.
Dietary targeting of CNBP to rein in the EREG-EGFR cascade and restore homeostasis in colitis-associated colorectal cancer.
Zhang T, Zhou L, Wang B … +12 more , Wang M, Zhu Y, Liu Y, Zhang T, Liu Q, Xiao C, Kong L, Xu Q, Zhang B, Qu J, Li S, Sun Y
Int J Biol Sci · 2026 · PMID 41943842 · Full text
Emerging evidence has linked high dietary fructose intake with adverse health outcomes, yet its role in colitis-associated colorectal cancer (CAC) remains underexplored. Here, we demonstrate that high fructose consumptio...
Emerging evidence has linked high dietary fructose intake with adverse health outcomes, yet its role in colitis-associated colorectal cancer (CAC) remains underexplored. Here, we demonstrate that high fructose consumption aggravates intestinal inflammation and significantly promotes tumorigenesis in an AOM/DSS-induced CAC model via activation of the EREG-EGFR signaling axis. We first developed the Food∩TCM database, which encompasses 112 medicine and food homologous TCM, along with their chemical compositions. Using the network-based pharmacological intelligence platform, we identified (kelp) and its bioactive components-fucoidan and dieckol-as promising dietary interventions. Dieckol was found to target the RNA/DNA-binding protein CNBP, which has traditionally been regarded as a positive regulator of pro-inflammatory gene expression, but here was shown to enhance its nuclear localization under inflammatory conditions and thereby repress transcription. Notably, fructose promoted O-GlcNAcylation-mediated stabilization and secretion of EREG in inflammatory fibroblasts, contributing to tumor progression. Together, these findings reveal the tumor-promoting effects of dietary fructose in CAC and highlight CNBP as a key regulator restraining expression. Our findings underscore the significance of integrating food-based strategies into chronic disease prevention, and support the development of -derived compounds as safe, long-term dietary agents for managing colitis-associated colorectal cancer.
Orphan Nuclear Receptor NR4A1 Promotes Proliferation and Osteogenic Differentiation of Valvular Interstitial Cells through Activation of CCND2.
Shen Q, Zhang C, Jiang C … +8 more , Liu Z, Fan L, Luo H, Qian X, Fan Z, Yao D, Dong N, Shi J
Int J Biol Sci · 2026 · PMID 41943841 · Full text
Calcific aortic valve disease (CAVD), the most common human valve disease on a global scale, ranks and persists as an unaddressed clinical challenge. This is primarily attributed to the absence of efficacious pharmacolog...
Calcific aortic valve disease (CAVD), the most common human valve disease on a global scale, ranks and persists as an unaddressed clinical challenge. This is primarily attributed to the absence of efficacious pharmacological approaches. The Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1), intricately associated with the pathogenesis of multiple cardiovascular diseases, has emerged as a pivotal target for the diagnosis and treatment of numerous ailments. However, the specific molecular mechanisms and the functional significance of NR4A1 in the pathogenesis of CAVD are yet to be comprehensively elucidated. By performing in-depth analyses on human aortic valve tissues and carrying out functional investigations using primary valvular interstitial cells (VICs), we were able to demonstrate that NR4A1 significantly facilitated cellular proliferation and intensifies the osteogenic differentiation process of VICs. Evidently, this is reflected in the elevated expression of key osteogenic markers, namely runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP). Mechanistically, the pro-calcific effects were achieved via NR4A1-dependent modulation of the cell cycle regulatory protein Cyclin D2 (CCND2). Significantly, investigations employing ApoE mice maintained on a high-fat Western diet demonstrated that pharmacological suppression of NR4A1 efficiently mitigated the advancement of aortic valve calcification. These discoveries not merely determine NR4A1 to be a crucial modulator in cellular proliferation, thereby accelerating valvular calcification, but also present compelling evidence advocating for targeting NR4A1 may represent a potential therapeutic strategy for CAVD.
Cellular and Molecular Neuro-Bone Cell Interactions Drive Alveolar Bone Remodeling During Orthodontic Mechanical Loading.
Fang X, Liao C, Wan J … +6 more , Jiang C, Yi Y, Wang J, Chen Q, Lin J, Chen X
Int J Biol Sci · 2026 · PMID 41943840 · Full text
Orthodontic tooth movement (OTM) is a biomechanically driven process governed by dynamic cellular and molecular signaling interactions between neural and skeletal systems. This review synthesizes current evidence on neur...
Orthodontic tooth movement (OTM) is a biomechanically driven process governed by dynamic cellular and molecular signaling interactions between neural and skeletal systems. This review synthesizes current evidence on neuron-bone cell crosstalk and the coordinated involvement of immune and vascular components in regulating alveolar bone remodeling during OTM. Key neural contributors include sensory neurons (nociceptors), autonomic neurons, central nervous system (CNS) circuits, and Schwann cells, which communicate with osteoblasts, osteoclasts, and periodontal ligament cells to modulate their proliferation, differentiation, and functional activity. These interactions are mediated by defined signaling pathways, including neuropeptide signaling (CGRP-CLR, SP-NK1, NGF-TrkA, BDNF-TrkB), axon guidance signaling (Sema3A-PlexinA/Nrp1), adrenergic signaling (β2-AR-dependent pathways), and intracellular cascades such as Rac1-β-catenin, RhoA/ROCK2, and Notch3. Sensory nerves function as primary initiators by releasing neuropeptides that promote osteoclastogenesis in pressure zones and osteogenesis in tension zones, while simultaneously shaping local immune responses and vascular remodeling. The autonomic nervous system exerts context-dependent regulation, with sympathetic signaling favoring bone resorption and parasympathetic pathways emerging as modulators of osteogenesis and neurovascular homeostasis. CNS circuits integrate sensory and autonomic inputs to coordinate OTM kinetics and pain perception. Together, these neuro-osteogenic signaling networks define mechanistic targets for improving orthodontic outcomes and pain management via neuromodulation.
Budding Yeast Ubiquitin Ligases Rad5 and Rad18 Bind a Novel PCNA Surface, which Is Required for their Functions in DNA-Damage Tolerance.
Fan L, Du Y, Novecosky A … +2 more , Luo Y, Xiao W
Int J Biol Sci · 2026 · PMID 41943839 · Full text
DNA-damage tolerance (DDT) is a highly regulated pathway to resume DNA synthesis in the presence of replication-blocking lesions. In budding yeast , DDT is mediated by sequential ubiquitination and sumoylation of prolife...
DNA-damage tolerance (DDT) is a highly regulated pathway to resume DNA synthesis in the presence of replication-blocking lesions. In budding yeast , DDT is mediated by sequential ubiquitination and sumoylation of proliferating cell nuclear antigen (PCNA). Rad18 and Rad5 are two E3 ligases responsible for PCNA mono- and poly-ubiquitination, respectively, at its K164 residue. Although Rad18 and Rad5 have been reported to interact with PCNA, they do not contain known PCNA-binding domains like a PCNA interaction peptide (PIP) box. In this study, we performed extensive mapping by a yeast two-hybrid assay and delineated PCNA-binding regions within 40 residues in both Rad18 and Rad5; amino acid sequence alignment revealed that they share a previously uncharacterized sequence defined as a LxLF motif in this study. Interestingly, Rad5 and Rad18 interact with PCNA on same surface distinct from the PIP box-binding sites. Site-specific mutagenesis confirmed that this LxLF motif is required for the DDT functions of Rad18 and Rad5 possibly through affecting PCNA mono- and poly-ubiquitination, respectively. In addition, an adjacent HIRAN domain in Rad5, known to bind 3' DNA ends to drive replication fork reversal, is also required for the PCNA interaction and DDT functions, consistent with previous reports.
Metabolic-Immune Coupling in Urologic Cancers: Macrophage Reprogramming as a Therapeutic Nexus.
Huang W, Li W, Shangguan W … +9 more , Yang L, Li Z, Sun B, Ma C, Yang X, Peng P, Zhao J, Cheng B, Wu P
Int J Biol Sci · 2026 · PMID 41943838 · Full text
Therapeutic responsiveness in urologic cancers is gated by metabolic-immune coupling that conditions tumor-associated macrophages (TAMs). Myeloid-dominated "cold" ecosystems blunt antigen handling, phagocytosis, and traf...
Therapeutic responsiveness in urologic cancers is gated by metabolic-immune coupling that conditions tumor-associated macrophages (TAMs). Myeloid-dominated "cold" ecosystems blunt antigen handling, phagocytosis, and trafficking, limiting the benefit of immune-checkpoint inhibitors (ICIs). This review focuses on three high-value axes that shape TAM state and niche: the lactate-pH / hypoxia-HIF-VEGF axis that enforces acidic, adenosinergic suppression and angiogenic programs; lipid rafts axis that stabilizes inhibitory hubs (e.g., PI3K-AKT/TREM2) and skews phagocytosis/antigen presentation; and ferroptosis-redox axis control that sets inflammatory versus tolerogenic set-points. The review further outlines pharmacodynamic anchors-hyperpolarized C-pyruvate MRI (k), soluble ANGPT2, and spatial NT5E/ADORA2A modules-to operationalize a bench-to-biomarker-to-bedside loop using organoid-immune co-cultures, humanized/xenograft systems, and tumor slices. This framework prioritizes adaptive enrichment for glycolysis- or adenosine-high tumors, rational timing/sequencing with ICIs, and avoidance of global myelosuppression. Collectively, metabolism-informed TAM re-education offers a route to convert myeloid-dominated "cold" ecosystems into treatment-responsive states across urologic cancers.
CFAP251 Deficiency Induces Male Infertility and PCD-like Ciliary Defects by Disrupting TUBB4B and SLC25A4 Recruitment in Humans and Mice.
Liu L, Wang Z, Zhou Y … +10 more , Tang D, Hua R, Li K, Wang G, Yang F, Liu C, Cao Y, Wu H, Gao Y, He X
Int J Biol Sci · 2026 · PMID 41943837 · Full text
Mutations in the gene have been identified as causative for morphology and motility abnormalities in spermatozoa of infertile males, manifesting as multiple morphological abnormalities of the sperm flagella (MMAF). Howe...
Mutations in the gene have been identified as causative for morphology and motility abnormalities in spermatozoa of infertile males, manifesting as multiple morphological abnormalities of the sperm flagella (MMAF). However, the mechanism underlying CFAP251-associated MMAF remains poorly understood, and the role of CFAP251 deficiency in PCD remains unclear. This study aimed to elucidate the pathogenic mechanism linking CFAP251 deficiency to human male infertility and to determine whether CFAP251 plays an active role in both flagella and cilia across species. A knockout mouse line was generated on a C57Bl/6J strain. mutations were identified by whole-exome sequencing on probands from Han Chinese families with primary infertility and MMAF. The knockout mouse model replicated the MMAF and male infertility phenotypes observed in humans for the first time. Moreover, the knockout mouse and one patient showed PCD-like symptoms, including tinnitus, seasonal cough, and radiological findings of coarsened lung markings and solitary pulmonary bulla associated with chronic bronchitic inflammation. Mechanistically, CFAP251 was confirmed to interact with TUBB4B, and its disruption led to the downregulation of TUBB4B, impairing spermiogenesis and ciliary function. Furthermore, CFAP251 was found to interact with the mitochondrial protein SLC25A4, suggesting a role in regulating energy transport. Favorable outcomes following ICSI were observed, with the successful birth of healthy offspring in four patients caused by variants. These included two cases with two novel homozygous splice-altering variants (c.1535+1G>C and c.1269+2T>C) and two previously reported MMAF cases. Our findings highlight the underlying risk of male infertility and PCD-like ciliary defects associated with and provide a valuable reference for personalized genetic counselling and clinical treatment of affected individuals.
CRISPR/Cas9 Screening Reveals that UBE2L3 Modulates Autophagic Flux through TSC2 Ubiquitination and Potentiates PD-1 Blockade in Triple-Negative Breast Cancer.
Xu J, Cheng L, Ma S … +8 more , Gan C, Chai J, Zheng X, Hu L, Ling M, Zhang M, Zhao B, Cheng H
Int J Biol Sci · 2026 · PMID 41943836 · Full text
Triple-negative breast cancer (TNBC), a distinct breast cancer subtype, poses significant challenges to conventional therapeutic approaches, and effective targeted therapies are limited. CRISPR/Cas9 library screening has...
Triple-negative breast cancer (TNBC), a distinct breast cancer subtype, poses significant challenges to conventional therapeutic approaches, and effective targeted therapies are limited. CRISPR/Cas9 library screening has demonstrated unprecedented efficiency and revolutionary potential in the identification of therapeutic targets. In this study, we performed CRISPR/Cas9 library screening and identified the E2 ubiquitin-conjugating enzyme UBE2L3 as a critical regulatory factor in the progression of TNBC. Loss of UBE2L3 restricted tumor cell growth by modulating autophagy in TNBC cells. Mechanistically, UBE2L3 downregulation led to increased tuberous sclerosis complex 2 (TSC2) expression, suppressing mTOR activity and altering autophagic processes in tumor cells. This regulation was mediated through the interaction between UBE2L3 and the E3 ubiquitin ligase SMURF2, which together control TSC2 protein ubiquitination and degradation. Autophagy and the tumor microenvironment are closely associated, and we observed that UBE2L3 knockdown in TNBC tumors significantly increased CD8+ T lymphocyte infiltration and enhanced tumor sensitivity to anti-PD-1 therapy. Collectively, our findings provide a theoretical foundation for considering UBE2L3 as a potential therapeutic target in TNBC.
CBX8 suppresses autophagy-dependent senescence in colorectal cancer by modulating the mTOR signaling pathway.
Li T, Zhang E, Liu X … +9 more , Zhou H, Zhang P, Zhang C, Zhang X, Wu N, Gong S, Ren Z, Ding J, Zhang Y
Int J Biol Sci · 2026 · PMID 41943835 · Full text
Colorectal cancer (CRC) is among the most common cancers worldwide. Cellular senescence, characterized by an irreversible state of growth arrest, has been recognized as a promising therapeutic strategy for combating canc...
Colorectal cancer (CRC) is among the most common cancers worldwide. Cellular senescence, characterized by an irreversible state of growth arrest, has been recognized as a promising therapeutic strategy for combating cancer. Here, the oncogenic role of Chromobox homolog 8 (CBX8) in CRC and its regulatory mechanisms in cell senescence and transcriptional regulation were systematically investigated. We demonstrated that CBX8 deficiency suppresses colorectal tumorigenesis and promotes tumor cell senescence in both and models. Mechanistically, CBX8 inhibits autophagy-dependent senescence in CRC by modulating the mTOR signaling pathway through transcriptional repression of DDIT4, a known negative regulator of mTOR. CBX8 achieves this by recruiting TRIM28 to bind the promoter region of DDIT4, thereby maintaining the H3K27me3 modification status and repressing expression of DDIT4. Furthermore, our findings highlight the therapeutic potential of CBX8 inhibitors in combination with senescence-targeting agents, which significantly enhances antitumor effects in CRC xenograft models. These results provide novel insights into the molecular mechanisms underlying CRC progression and underscore the potential of CBX8 as a therapeutic target for developing targeted therapies and senolytic-based anticancer strategies. This study advances our understanding of CRC pathogenesis and offers promising directions for precision medicine in CRC treatment.
Apigenin Suppresses Bladder Cancer via the SIRT6-NCOA2-PPARα Axis.
Liu Y, Shi ZD, Wei YF … +10 more , Jiang SY, Patel H, Liu QZ, Dong Y, Liu YF, Hao L, Gao S, Yang DH, Li Q, Han CH
Int J Biol Sci · 2026 · PMID 41943834 · Full text
Protein acetylation is increasingly recognized as a key regulator of tumor progression, yet natural compounds capable of modulating this modification remain poorly defined. Apigenin, a dietary flavonoid suppresses bladde...
Protein acetylation is increasingly recognized as a key regulator of tumor progression, yet natural compounds capable of modulating this modification remain poorly defined. Apigenin, a dietary flavonoid suppresses bladder cancer progression based on functional assays and dynamic xenograft models. Mechanistically, we applied an integrated multi-omics approach to unravel that apigenin enhances SIRT6-mediated deacetylation of Nuclear Receptor Coactivator 2 (NCOA2), leading to site-specific deacetylation of NCOA2 at lysine 780 and 785. This modification potentiates PPARα transcriptional activity, reprograms cellular energy metabolism, and disrupts mitochondrial membrane potential. Clinically, reduced SIRT6 expression coupled with elevated NCOA2 and mitochondrial/β-oxidation markers correlates with metastatic progression in bladder cancer. Together, these findings identify a previously unrecognized SIRT6-NCOA2-PPARα signaling axis as a metabolic vulnerability in bladder cancer.
Clonotype-Resolved Single-Cell Multi-Omics Unlocks the Profile of Tumor-Infiltrating CD39⁺CD8⁺ T Cells and Enables Adoptive Cell Therapy for Solid Tumor.
Zhao Z, Wu X, Jin Q … +8 more , Yang X, Zhu W, Jiang N, Liu T, Li T, Fang F, Guo H, Yang R
Int J Biol Sci · 2026 · PMID 41943833 · Full text
Tumor-reactive T cells are central to cancer immunotherapy, and immune checkpoint inhibitors (ICIs) have revolutionized treatment by relieving immune suppression on tumor-reactive T cells, yet response rates remain subop...
Tumor-reactive T cells are central to cancer immunotherapy, and immune checkpoint inhibitors (ICIs) have revolutionized treatment by relieving immune suppression on tumor-reactive T cells, yet response rates remain suboptimal. Adoptive T cell therapy can supplement tumor-reactive T cells, but accurately identifying tumor-reactive CD8⁺ T cells within tumor-infiltrating lymphocytes (TILs) remains challenging. CD39 (ENTPD1) is a rate-limiting enzyme in adenosine metabolism, leading to the view that CD39 is associated with immune suppression because of the inhibitory function of adenosine in tumor immunity. However, its role in tumor-reactive CD8⁺ TIL endures as controversial. In this study, we reassess the tumor-reactive potential of CD39⁺CD8⁺ TILs using clonotype-resolved single-cell multi-omics. Compared to CD39⁻CD8⁺ TILs, CD39⁺CD8⁺ TILs exhibited features of proliferation, activation, and T cell-mediated cytotoxicity, alongside reduced TCR clonal diversity and increased TCR clonal expansion, indicating tumor reactivity. TCR-T cells engineered with TCRs from CD39⁺CD8⁺ TILs mediated robust antigen-specific killing . Importantly, reinfusion of CD39⁺CD8⁺ TILs significantly inhibited tumor growth and demonstrated favorable safety . At the patient level, we further demonstrated that CD39⁺CD8⁺ TILs are enriched for effector programs and pathways linked to T-cell activation and cytotoxicity, and exhibit reduced TCR clonal diversity with pronounced clonal expansion. The intratumoral abundance of CD39⁺CD8⁺ TILs also correlated with earlier tumor stage and improved overall survival, and a CD39⁺CD8⁺ TIL-derived gene signature predicted ICI response and prognosis, supporting CD39 as a practical biomarker to enrich tumor-reactive CD8⁺ TILs and to improve adoptive cell transfer strategies in future clinical practice.
Ubiquitin-conjugating Enzymes in Cancer.
Yao Z, Peng T, Dong H … +4 more , Liao Y, Miao K, Qin JJ, Guan X
Int J Biol Sci · 2026 · PMID 41943832 · Full text
Ubiquitin-conjugating enzymes (E2s) are emerging as critical regulators of oncogenic signaling networks by modulating protein stability, localization, and interactome dynamics. Distinct E2s orchestrate ubiquitin chain to...
Ubiquitin-conjugating enzymes (E2s) are emerging as critical regulators of oncogenic signaling networks by modulating protein stability, localization, and interactome dynamics. Distinct E2s orchestrate ubiquitin chain topology to drive cancer hallmarks including proliferation, immune evasion, metastasis, and metabolic reprogramming. Despite their central role in the ubiquitin-proteasome system, E2s remain underexploited as therapeutic targets. This review systematically maps E2-mediated signaling mechanisms across cancer types and proposes translational strategies for E2-targeted intervention.
Suppression of ASNS expression by VHL-mediated ubiquitination hinders the progression of renal cell carcinoma through enhancing JUP expression and inhibiting PI3K-AKT and MAPK pathways.
Yang W, Liu T, Ying W … +4 more , Lu M, Xia D, Tang T, Peng D
Int J Biol Sci · 2026 · PMID 41943831 · Full text
Renal cell carcinoma (RCC) is a metabolic disorder and gene inactivation is recognized as a crucial event in RCC progression. Investigating the specific metabolite that differ in mutant RCC and understanding how VHL reg...
Renal cell carcinoma (RCC) is a metabolic disorder and gene inactivation is recognized as a crucial event in RCC progression. Investigating the specific metabolite that differ in mutant RCC and understanding how VHL regulates the metabolite may offer new insights into the underlying mechanisms of RCC. First, we employed untargeted metabolomics and ELISA to identify and confirm the differential metabolite in the plasma and tumor tissues of mutant RCC patients. Then, we demonstrated the importance of the differential metabolite in RCC progression through cell phenotype and animal experiments. Finally, we utilized western blotting, immunoprecipitation, ubiquitination modification proteomics, TMT proteomics, and RNA sequencing to elucidate the regulatory mechanisms of VHL on the metabolite. By analyzing the metabolomics data from plasma and tumor tissues alongside subsequent expression validation, we identified L-Asparagine (L-Asn) as the differential metabolite in mutant RCC, with its levels significantly decreased in these tumors. L-Asn was found to promote the growth and metastasis of RCC cell lines and mouse orthotopic renal tumors. Mechanistically, VHL interacted with L-Asparagine synthase (ASNS) and facilitated its ubiquitination, leading to decreased ASNS expression, and ASNS overexpression activated PI3K-AKT and MAPK signaling pathways by binding to Junction plakoglobin (JUP) and inhibiting its expression. Conversely, use of an ASNS inhibitor significantly restrained the growth and metastasis of RCC cells and . In summary, our findings highlighted the critical role of L-Asn in RCC and identified ASNS as a novel substrate for VHL-mediated ubiquitination, presenting a potential new target for RCC treatment.
Mechanistic Insights into the FOXM1/BUB1 axis-Mediated Oncogenic Signaling in Hepatocellular Carcinoma.
Wang S, Mao Y, Zeng T … +6 more , Yong T, An Y, Li J, Wang Y, Yang X, Guan Q
Int J Biol Sci · 2026 · PMID 41943830 · Full text
The development of novel therapeutic strategies for advanced and metastatic hepatocellular carcinoma (HCC) remains an urgent clinical need. Despite suboptimal efficacy, the breakthrough of tyrosine kinase inhibitors in H...
The development of novel therapeutic strategies for advanced and metastatic hepatocellular carcinoma (HCC) remains an urgent clinical need. Despite suboptimal efficacy, the breakthrough of tyrosine kinase inhibitors in HCC treatment therapy underscores the advantage of targeted therapy. Therefore, innovative targeted therapies are urgently needed to enhance treatment efficacy, decrease recurrence rates, and improve patient survival outcomes. The forkhead box M1 (FOXM1) transcription factor serves as a master regulator of oncogenic signaling networks that drive cancer progression. Our study identified budding uninhibited by benzimidazoles 1 (BUB1) as a crucial downstream effector of FOXM1, with demonstrated direct protein-protein interaction. Moreover, FOXM1 directly bound to the GTAAACC motif at the -293 bp region of the BUB1 promoter and activated its transcription, thereby driving HCC cell proliferation. Mechanism studies have shown that the FOXM1/BUB1 axis regulated multiple oncogenic processes in HCC, including cell proliferation, DNA repair, G2/M cell cycle transition, stemness, invasion, and migration. Knockdown of BUB1 significantly sensitized HCC cells and xenograft tumors to the FOXM1 inhibitor FDI-6. Furthermore, combined pharmacological inhibition of FOXM1 (FDI-6, RCM-1, thiostrepton) and BUB1 (BAY-1816032) synergistically inhibited the proliferation of HCC cells and xenograft tumors. These findings establish FOXM1-mediated BUB1 upregulation as a key driver of HCC malignancy. Targeting the FOXM1/BUB1 axis represents a promising therapeutic strategy for the treatment of advanced and metastatic HCC, offering new opportunities for HCC therapy.
Investigating the Mechanistic Link Between Lactate-Induced Histone Lactylation and Cellular Senescence in Osteoarthritis Chondrocytes: Implications for Therapy.
Zuo R, Wu C, Lin Z … +10 more , Kong L, Wang F, Zhang X, Wei J, Lin Y, Yang E, Kang Q, Zhao S, Guan J, Zhao J
Int J Biol Sci · 2026 · PMID 41943829 · Full text
Chondrocyte senescence accelerates osteoarthritis (OA) progression, with dysregulated glycolysis potentially driving this process through lactate accumulation and histone lactylation. However, the mechanistic connection...
Chondrocyte senescence accelerates osteoarthritis (OA) progression, with dysregulated glycolysis potentially driving this process through lactate accumulation and histone lactylation. However, the mechanistic connection between lactate-induced lactylation and cellular senescence in OA chondrocytes remains poorly understood. This study elucidates this relationship and explores its therapeutic relevance. Using clinical OA cartilage, animal models, and IL-1β-stimulated chondrocytes, we demonstrated enhanced glycolysis and senescence activities. Increased glycolytic activity and lactate accumulation promoted cellular senescence in the OA microenvironment. Elevated lactate levels increased global lactylation, with H4K12la as the predominant mark. H4K12la-targeted CUT&TAG analysis identified TRIM29 as a key regulator. H4K12la promotes TRIM29 transcription, which activates the PI3K-AKT pathway via direct and EGFR-mediated mechanisms, leading to autophagy inhibition and senescence. Interventions such as SIRT1 overexpression or intra-articular oxamate injection reduced lactylation, inhibited glycolysis, and mitigated cartilage degeneration. These findings demonstrate that glycolytic lactate-induced H4K12la fosters senescence through TRIM29-mediated PI3K-AKT activation, highlighting the inhibition of glycolysis or lactylation as a promising therapeutic strategy for OA.
HMGA1 Activates FGFBP1 Transcription to Enhance Angiogenesis Induction and Tumor Progression via FGF2/FGFR1 Pathway.
Zhang Z, Xiong Y, Li M … +9 more , Wang S, Liu Z, Wang G, Zhang H, Yang X, Liu G, Zhang D, Wu H, Huang S
Int J Biol Sci · 2026 · PMID 41943828 · Full text
High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallm...
High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). silencing suppressed oncogenic properties and reduced tumor initiating cells in HNSCC xenograft mice. RNA sequencing revealed that HMGA1 regulated transcriptional networks involved in tumor progression and angiogenesis, including the gene. HMGA1 directly binds to the promoter to induce its expression. This upregulation increased secretion of FGFBP1's target, FGF2. Interestingly, disrupting FGFBP1 via gene silencing or the FGFR1 inhibitor PD166866 recapitulated phenotypes observed with silencing. Blocking , , or FGFR1 also reduced stromal formation and increased tumor necrosis. In human HNSCC, the combined analysis of HMGA1 and FGFBP1 provides a more detailed evaluation of patient prognosis. Our findings highlight a novel paradigm where HMGA1 and FGFBP1 drive tumor progression and angiogenesis, presenting them as potential therapeutic targets for HNSCC.
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