International Journal of Biological Sciences最新文献

Gut microbiota plays a central role in programming host metabolic function and immune modulation in both health and disease. Microbial dysbiosis leads to an increase in opportunistic pathogens and a reduction in beneficial bacteria, which collectively result in the excessive production of detrimental metabolites, particularly uremic toxins such as indoxyl sulfate and trimethylamine-N-oxide, while concurrently decreasing beneficial metabolites, such as short-chain fatty acids and tryptophan catabolites, including indole-3-aldehyde. The accumulation of harmful metabolites and depletion of protective metabolites contribute to fibrosis progression through various mediators, including the renin-angiotensin system, reactive oxygen species, Toll-like receptor 4, aryl hydrocarbon receptor, inhibitor of kappa B/nuclear factor kappa B, and Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathways. This review highlights the pathogenic link between gut microbiota and kidney damage via the gut-kidney axis, encompassing acute kidney injury (AKI) and chronic kidney disease (CKD). Innovative therapeutic strategies, including microbial therapeutics (such as probiotics, prebiotics, and synbiotics), natural products (such as neohesperidin, isoquercitrin, and polysaccharides), and fecal microbiota transplantation, have been proposed to restore microbial balance and improve kidney function. Targeted modulation of the gut microbiota offers a promising strategy for developing novel treatments in AKI, CKD, and the transition from AKI-to-CKD. This approach has the potential to prevent or mitigate these conditions and their complications.

Inosine monophosphate dehydrogenase 2 (IMPDH2) is implicated in survival and proliferation of cancer cells because of its role in guanine nucleotide biosynthesis. This study evaluates the efficacy of AVN944, an IMPDH2 inhibitor, as a treatment for Ewing's sarcoma, a challenging malignancy in pediatric and young adult patients. Gene expression data, as well as clinical outcomes for sarcoma patients, from The Cancer Genome Atlas (TCGA) were analyzed to determine the association between IMPDH2 expression and survival. Human Ewing's sarcoma cell lines and xenograft models were used to evaluate the cellular and in vivo effects, respectively, of AVN944. Various cellular assays, including western blotting, MTT, BrdU incorporation, and colony formation assays, were conducted to assess the impact of AVN944 on proliferation, viability, and apoptosis. IC₅₀ values were calculated from dose-response curves. Sarcoma patients with high expression of IMPDH2 showed a trend towards poorer overall survival. In vitro, AVN944 decreased the viability and proliferation of TC71 and SK-ES-1 Ewing's sarcoma cell lines significantly, and in a dose-dependent manner. The drug induced G₁ cell cycle arrest and apoptosis, as evidenced by increased expression of pro-apoptotic markers and reduced expression of cell cycle proteins. In vivo, AVN944 effectively inhibited tumor growth in xenograft models without notable toxicity. The IC₅₀ of AVN944 was approximately 0.05 μM for both TC71 and SK-ES-1 cell lines. Thus, AVN944 displays potent anti-tumor activity against Ewing's sarcoma cells both in vitro and in vivo by inhibiting IMPDH2. The inhibitor causes cell cycle arrest and apoptosis, significantly reducing tumor viability and proliferation. These findings highlight the therapeutic potential of targeting nucleotide biosynthesis pathways in Ewing's sarcoma, suggesting that AVN944 could be a valuable addition to existing treatment protocols. Further clinical investigations are recommended to validate these preclinical outcomes and to explore integration of AVN944 into treatment regimens for Ewing's sarcoma.

Mitochondrial Acyl-Coenzyme Synthetase Short Chain Family Member-1 (ACSS1) converts free acetate into acetyl-coenzyme A (acetyl-CoA), regulated, in part, by acetylation at lysine 635 (ACSS1-K635). We challenged our ACSS1 constitutive acetylation mimic knock-in (K635Q) mice by injecting a β3-adrenergic receptor agonist, CL-316243 (CL), to induce a thermogenic response. Strikingly, we show that Acss1^K635Q/K635Q mice exhibit hypothermia and acute metabolic crisis following CL stimulus, as shown by significantly reduced oxygen consumption, carbon dioxide production, respiratory exchange ratio, and heat production. We also observed histological differences in both brown adipose tissue (BAT) and subcutaneous white adipose tissue (WAT), accompanied by altered expression and regulation of lipogenic enzymes and Uncoupling Protein 1 (UCP1) in Acss1^K635Q/K635Q . In contrast to wild-type adipose tissues, Acss1^K635Q/K635Q did not show changes in acetyl-CoA and acetate levels in response to CL, and mitochondria isolated from BAT displayed impaired respiration on palmitate. Lastly, beige adipocytes differentiated ex vivo from Acss1^K635Q/K635Q mice showed altered response to the adenylate cyclase stimulator, forskolin, with unresponsive mitochondria and lipogenic lipid droplets, and lower fatty acid oxidation activity. These results suggest that non-acetylated ACSS1 plays an essential role in thermoregulation and the ability to metabolize free fatty acids.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD⁺ salvage pathway and a promising therapeutic target in cancer. Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation. While acquired resistance in cancer cell lines has been linked to target mutations, increased drug efflux, and metabolic reprogramming, innate resistance mechanisms have been poorly studied. Addressing this gap is crucial for identifying patient subgroups that are most likely to benefit from NAMPT-targeted therapies. Advanced castration resistance prostate cancer (CRPC) lacks effective targeted treatments. Among its heterogeneous subtypes, stem cell-like CRPC (CRPC-SCL) is characterized by independence from androgen receptor (AR) signaling, dependency on YAP/TAZ, and mesenchymal traits. In this study, we identify the YAP/nicotinamide N-methyltransferase (NNMT) axis as a key regulator of innate sensitivity to FK866 in stem-like mesenchymal CRPC cells. Using genetic and pharmacological models, we show that YAP or NNMT silencing rescues PC3 cells from FK866-induced apoptosis, endoplasmic reticulum stress, and NAD(H) depletion. Metabolomic profiling confirmed that NNMT activity depletes nicotinamide, sensitizing cells to FK866. We further validated NNMT upregulation across clinical CRPC-SCL datasets, where it strongly correlates with mesenchymal and therapy-resistant phenotypes. Murine prostate cancer cells with mesenchymal/stemness phenotypes (DVL3-SCM), that exhibit NNMT overexpression and high aggressiveness in vivo, also show increased sensitivity to FK866 compared with their parental counterparts (DVL3-PAR). In conclusion, we identify the YAP/NNMT axis as a determinant of innate sensitivity to NAMPT inhibition in prostate cancer. These findings support the use of NNMT as a predictive biomarker for NAD⁺-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers.

The senescence-associated secretory phenotype (SASP) exerts dual roles in tumor suppression and progression, yet how it is regulated in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we identify LIM homeobox 1 (LHX1) as a key transcriptional suppressor of STING, whose downregulation enables evasion of SASP-mediated tumor surveillance. Notably, high LHX1 expression correlated with poor prognosis in HNSCC patients. Mechanistically, LHX1, in complex with LDB1, directly bound to the STING promoter to mediate transcriptional repression via the deposition of the repressive histone mark H3K9me3, thereby blocking SASP activation. Depletion of LHX1 restored STING-dependent SASP and impaired cancer stem cell self-renewal. Therapeutic disruption of the LHX1-LDB1 complex using engineered peptides re-activated STING signaling, induced SASP, and significantly suppressed tumor growth. In this study, we employed human and mouse-derived HNSCC cell lines, xenograft models, and clinical samples to assess the functional relevance of LHX1 in regulating SASP and tumor progression. Our findings reveal LHX1 as a master transcriptional repressor of STING-mediated senescence and highlight the therapeutic potential of targeting the LHX1-LDB1 axis to restore tumor-suppressive SASP in HNSCC.

Artificial intelligence (AI)-driven research frameworks are reshaping the boundaries of biomedical discovery. The Virtual Lab exemplifies this transformation, assembling large language model (LLM) agents into coordinated scientific teams functioning as investigators, specialists, and critics. The system autonomously designed, scored, and refined nanobody candidates against emerging SARS-CoV-2 variants, and subsequently validated them experimentally. These findings demonstrate how AI can move beyond prediction and retrieval to serve as an active collaborator in hypothesis generation, experimental design, and translational application. As technology continues to advance, the convergence of artificial intelligence and quantum computing is expected to give rise to a new era of Quantum AI enabled biomedical research. This integration will accelerate discovery speed, enhance precision, and foster interdisciplinary collaboration, opening unprecedented opportunities for data-driven innovation in the life sciences.

Bone homeostasis relies on the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. Disruption of this balance leads to osteoporosis, a highly prevalent bone disease with substantial health impacts in middle-aged and older adults. There is accumulating evidence linking the development of osteoporosis to alterations in the gut microbiota and its metabolite profile. The gut metabolite indole and its derivatives were shown to have beneficial effects in multiple metabolic diseases. However, their effects on bone homeostasis remain unclear. This study identified alterations in the gut microbiota and decreases in levels of tryptophan metabolites in an ovariectomized (OVX) estrogen deficiency-induced osteoporosis mouse model, characterized by decreased abundance of Lactobacillus and Clostridium species in the gut and reduced serum levels of indoleacrylic acid (IA), indoleacetic acid (IAA), and indolepropionic acid (IPA). IA showed a significant positive correlation with bone mass. Specifically, IA inhibited RANKL-induced aryl hydrocarbon receptor (AhR) and c-Fos expression, reducing nuclear translocation of p-p65 in bone marrow macrophages (BMMs), ultimately resulting in suppression of osteoclast resorption activity. AhR acts as a key positive regulator in the process of osteoclastogenesis, and its overexpression restored IA-mediated inhibition of osteoclast formation. In vivo, daily IA supplementation protected mice against OVX-induced bone loss, with higher PINP and lower CTX-1 levels. Taken together, these findings identified IA as a promising therapeutic candidate capable of suppressing osteoclastogenesis through an AhR-dependent mechanism, providing mechanistic insight and a potential strategy for the treatment of postmenopausal osteoporosis.

R-spondins are a family of four secretory proteins reported to be Wnt agonists. Among them, R-spondin 4 (RSPO4) is unique, with the lowest binding affinity towards ZNRF3/RNF43 and the lowest efficacy in regulating Wnt/β-catenin signaling. RSPO4 has been shown to play important roles in nail development, liver fibrogenesis and periodontitis, while its role in cancerous context remains largely unknown. In this study, we performed multi-omic analysis on transcriptional expression and methylation pattern of RSPO4. In vitro cell-based assays were performed to evaluate the functionality of RSPO4. Through cancer epigenomics, we identified RSPO4 as a candidate tumor suppressor with tumor-specific epigenetic inactivation. We further found that RSPO4 is readily expressed in human normal tissues, but frequently downregulated or silenced in multiple cancer types due to its promoter CpG methylation. Functional studies showed that RSPO4 inhibited tumor cell proliferation, migration, invasion and stemness, through antagonizing canonical and non-canonical Wnt signaling. Mechanistically, RSPO4 exerted suppressive effects on Wnt signaling in an LGR4/5- and ZNRF3- dependent manner, through promoting LRP6 degradation and ZNRF3 stabilization. Our study revealed a novel role of RSPO4 as a tumor suppressor through antagonizing Wnt signaling, which provides important implications for development of diagnostic biomarkers and targeted therapy.

Monocyte-macrophage plays a central role in innate immunity, tissue homeostasis maintenance, and disease progression. These phagocytes, which originate from blood monocytes or embryonic sources, are imperative for inflammatory responses, tissue repair, and bone remodeling. In orthopedic diseases, including osteoarthritis, rheumatoid arthritis, osteoporosis, and fractures, changes in histone acetylation are key to regulating macrophage gene expression, polarization, differentiation into osteoclasts, and pathological bone remodeling. Histone acetylation (mediated by histone acetylases) and deacetylation (mediated by histone deacetylases) directly influence important transcription factors in the monocyte-macrophage system by dynamically modulating chromatin accessibility. This review systematically examines the epigenetic network involving histone acetylation and deacetylation monocyte-macrophage, exploring its translational potential in bone-related diseases.

High lymphocyte infiltration and T cell exhaustion characterize the tumor microenvironment in renal cell carcinoma (RCC). Protein tyrosine phosphatase N22 (PTPN22), a protein tyrosine phosphatase that mediates proteins tyrosine dephosphorylation, is a negative regulator of T cell receptor signaling, but its role in tumor cells has been underappreciated. PTPN22 is highly expressed in RCC cells and positively correlated with PD-L1 protein expression. CBL was newly identified as a substrate of PTPN22, and our study reveals for the first time that CBL mediates the K48-linked ubiquitination of PD-L1. PTPN22 specifically interacts with CBL, catalyzing the dephosphorylation of tyrosine 700 and inhibiting CBL binding to PD-L1, thereby preventing CBL-mediated ubiquitination and degradation of PD-L1. This stabilization of PD-L1 promotes T cell exhaustion and immunosuppression. Through screening of traditional Chinese medicine monomers, we identified curcumin as a potential PTPN22 inhibitor. Curcumin reduces PTPN22 stability and PTPN22 expression by directly binding to PTPN22. In vivo experiments demonstrated that combining curcumin with immune checkpoint inhibition (ICIs) further promotes T cell activation, inhibits Tregs infiltration, and enhances ICIs efficacy against tumor growth. Therefore, PTPN22 represents a therapeutic target for improving T cell exhaustion in RCC and enhance ICIs efficacy through CBL-mediated ubiquitination and degradation of PD-L1.