International Journal of Biological Sciences最新文献

Metabolic disturbances of decidual macrophages (dMφs) may contribute to the pathology of miscarriage, yet the underlying mechanisms remain poorly defined. Here, we document upregulated tryptophan metabolic pathway in dMφs from women with unexplained recurrent pregnancy loss (URPL), with increased kynurenine (KYN) levels in the decidua and elevated aryl hydrocarbon receptor (AHR) expression in dMφs. Excessive activation of the KYN-AHR axis compromises both mitochondrial and lysosomal integrity. This impairment facilitates the leakage of mtDNA into the cytoplasm and subsequent release into the extracellular space, thereby activating the cGAS-STING signaling cascade. Mechanistically, AHR directly binds to the xenobiotic response element within the CISH promoter region, promoting its transcription. The upregulation of CISH promotes the ubiquitination and degradation of ATP6V1A, disrupting lysosomal acidification and exacerbating mtDNA release. In vivo, excessive administration of KYN in pregnant mice increases the rate of embryo resorption, whereas pharmacological inhibition of AHR partially attenuates cGAS-STING pathway activation in dMφs and ameliorates fetal loss in an abortion-prone mouse model. Collectively, our findings describe a pivotal role for the AHR/CISH/ATP6V1A axis in orchestrating immune dysfunction within the decidua that may contribute to URPL, which sheds new light on the potential pathogenesis of URPL and paves the way for improving pregnancy outcomes.

Acetaldehyde (AcH), the first metabolite of ethanol, is an aversive and bioactive compound that plays a key role in modulating alcohol consumption and liver injury. The traditional notion is that AcH is primarily metabolized in the liver by aldehyde dehydrogenase 2 (ALDH2). However, our recent study suggests that the gut-liver ALDH2 axis, rather than the liver alone, plays a key role in metabolizing and clearing AcH partially via bile secretion. Aquaporin 8 (AQP8) is a membrane channel that localizes at the canalicular membrane of hepatocytes and is known to increase bile flow. Here, we identify hepatic AQP8 as an important channel of AcH excretion, mediating its efflux from hepatocytes into bile both with and without altering bile flow. We demonstrated that acute alcohol exposure enhanced AQP8-mediated bile flow and AQP8 promoted hepatic AcH clearance and increased alcohol consumption in both male and female mice. Furthermore, chronic alcohol exposure downregulated hepatic Aqp8 expression, whereas overexpression of hepatic Aqp8 alleviated dysregulated lipid metabolism and liver inflammation in a murine model of alcohol-associated liver disease (ALD). Collectively, our study uncovers a novel role for AQP8 in AcH secretion, demonstrating how this pathway influences both alcohol consumption and liver injury. These findings provide a foundation for exploring AcH excretion as a therapeutic target in alcohol use disorder and ALD.

Lung adenocarcinoma (LUAD) progression involves multistep molecular pathogenesis, with many critical mediators of malignant transformation yet to be fully characterized. Building upon our previous discovery of discoidin, CUB and LCCL domain containing 1 (DCBLD1) as a novel LUAD risk-associated gene, we systematically investigated its function and underlying mechanisms in LUAD. Intriguingly, DCBLD1 overexpression promotes cellular transformation in both bronchial epithelial cells and EGFR^L858R alveolar type II organoids, while its deficiency in DCBLD1^-/- mice significantly suppresses LUAD initiation. Mechanistic studies revealed that DCBLD1 drives oncogenesis through direct interaction with EGFR. Specifically, the intracellular domain of DCBLD1 competitively binds to EGFR, displacing the critical negative regulator PTP1B phosphatase. This displacement impairs EGFR dephosphorylation, leading to sustained receptor activation and subsequent hyperactivation of downstream PI3K/AKT and MAPK signaling cascades. The sustained signaling activation produces significant clinical implications for LUAD treatment. In therapeutic studies, DCBLD1 knockdown demonstrated substantial antitumor effects in both patient-derived organoid and xenograft models, independent of EGFR mutation status. These findings position DCBLD1 as a promising therapeutic target for LUAD patients, offering a potential strategy that complements current EGFR mutation-based approaches.

Bacillus Calmette-Guérin (BCG) remains the standard treatment for non-muscle invasive bladder cancer (NMIBC), yet approximately 30% of patients fail to respond. To enhance therapeutic efficacy, we developed rBCG-LTAK63, a recombinant BCG strain, as a novel immunotherapeutic candidate. In vitro, rBCG outperformed BCG in MB49 cell/splenocyte co-cultures by enhancing T cell activation and improving spheroid growth control. In vivo, rBCG demonstrated superior antitumor efficacy, significantly reducing the growth of subcutaneously implanted MB49 tumor cells. Immune profiling revealed that rBCG uniquely promoted systemic activation of both CD4⁺ and CD8⁺ T cells, alongside stronger activation of NK and dendritic cells in the spleen. Within the tumor microenvironment, rBCG increased immune cell infiltration, enhanced activation of CD8⁺ T cells and dendritic cells, and decreased the frequency of regulatory T cells, fostering a less immunosuppressive environment. Unlike parental BCG, rBCG-LTAK63 sustained a potent immunostimulatory profile, marked by robust activation of dendritic cells and effector T cells. Similar results were also observed in the orthotopic model, suggesting a translational potential of rBCG-LTAK63. Collectively, our findings demonstrate that rBCG outperforms conventional BCG and represents a promising strategy for improving NMIBC treatment.

Renal allograft interstitial fibrosis, a key pathological feature of chronic renal allograft dysfunction (CAD), is a critical determinant of long-term graft survival. However, its underlying molecular mechanisms remain incompletely understood. This study uncovers the central role of programmed cell death, particularly the novel PANoptosis modality, in the progression of CAD. PANoptosis integrates features of pyroptosis, apoptosis, and necroptosis, but does not fit within the confines of any single pathway, with its mechanisms previously undefined. By analyzing cell death patterns in CAD tissues through single-cell sequencing and validating findings via in vivo and in vitro experiments, this work demonstrates that in the context of chronic inflammation, tumor necrosis factor-alpha (TNF-α) modulates signal transducer and activator of transcription 1 (STAT1) through dual phosphorylation. This process directly induces tyrosine 701 phosphorylation and activates serine 727 phosphorylation via the p38 MAPK pathway. Phosphorylated STAT1 subsequently upregulates the PANoptosome sensor absent in melanoma 2 (AIM2), driving PANoptosis in renal tubular epithelial cells. This mechanism further exacerbates interstitial fibrosis by promoting the paracrine secretion of interleukin-6 and transforming growth factor-beta, which induces epithelial-mesenchymal transition (EMT) in adjacent tubular cells. These findings represent the first demonstration of the TNF-α/STAT1/AIM2 axis in triggering PANoptosis and its downstream EMT-fibrosis cascade, offering novel therapeutic targets for CAD intervention.

Disuse osteoporosis (DOP), a skeletal disorder triggered by insufficient mechanical loading, manifests as progressive bone mass deterioration and microarchitectural weakening. Piezo1, a key mechanosensitive ion channel expressed in bone cells, is implicated in maintaining skeletal homeostasis. Using a murine hindlimb unloading (HLU) model simulating microgravity-induced bone loss, we observed significant downregulation of Piezo1 expression in bone tissue and isolated bone marrow-derived mesenchymal stem cells (BMSCs). Systemic administration of the Piezo1 agonist Yoda1 attenuated HLU-induced osteopenia and improved bone formation capacity. Mechanistic studies in BMSCs demonstrated that Piezo1 activation promoted mitochondrial biogenesis. This effect required AMPK/SIRT1 signaling-dependent deacetylation of PGC-1α, leading to enhanced mitochondrial function, improved osteogenic differentiation, and reduced apoptosis. Critically, pharmacologic inhibition of SIRT1 abolished the osteoprotective effects of Yoda1 in vivo. These findings establish that mechanical unloading impairs Piezo1-mediated mechanotransduction in BMSCs, contributing to disrupted skeletal homeostasis, which can be mitigated by exogenous Piezo1 activation. Our results define a mechanism where Piezo1 integrates mechanical signals into the AMPK/SIRT1/PGC-1α signaling cascade to regulate mechanoadaptive bone formation, highlighting Piezo1 activation as a potential mechanism-based therapeutic strategy for disuse osteoporosis.

Lung cancer (LC), prostate cancer (PC), and breast cancer (BC) are the three most prevalent cancers that lead to bone metastasis (BoM). In this study, we conducted an integrated analysis of single-cell transcriptomic data from the primary tumors and BoM across PC, LC, and BC. We discover a novel subtype of tumor-associated macrophages (TAMs) that are positive both for matrix metalloproteinase 19 (MMP19) and receptor activator of nuclear factor-κB (RANK) expression (MMP19⁺ RANK⁺ TAMs). MMP19⁺ RANK⁺ TAMs demonstrate an increased level of M2 polarization and act as a critical driving factor for LC-BoM. MMP19⁺ RANK⁺ TAMs are organized in a ring-like arrangement surrounding the tumor nests, constructing a barrier structure that impedes the infiltration of CD8⁺ T cells into the tumor core in LC-BoM. RANKL inhibitor Denosumab has been shown to effectively reduce the level of M2 polarization, decrease the population of MMP19⁺ RANK⁺ TAMs, and disrupt their barrier structure. Denosumab facilitates the infiltration of CD8⁺ T cells into the interior of LC-BoM tissues. Based on this mechanism, we observed in both clinical cohorts and preclinical models that RANKL inhibitor can enhance the efficacy of immunotherapy in treating LC-BoM.

Huntington's disease (HD) is a rare, inherited neurodegenerative disorder caused by mutations in the huntingtin (HTT) gene. The classic concept is that HD is a degenerative disease that primarily affects the striatum, caused by a gain-of-function mutant mHTT that kills neurons. However, increasing evidence suggests that the effects of mHTT on development may be an alternative view of HD. Therefore, we describe the importance of HTT for neurodevelopment and then summarize the effects of mHTT on neurodevelopment that have been revealed so far in different models. Importantly, we provide new insights into the use of different models to study HD development, and propose new therapeutic strategies for intervening in HD early in development to improve disease progression. Furthermore, we explore potential connections between neurodevelopmental abnormalities and neurodegenerative processes in HD. This review provides a systematic synthesis of current knowledge regarding HD development and pathogenesis.

Acute kidney injury (AKI) often leads to incomplete recovery of renal function, progressing to chronic kidney disease (CKD). Key pathological features in the AKI-CKD transition include microvascular rarefaction and fibrosis. However, the direct effects of activated fibroblasts on microvasculature and endothelial cells remain unclear. We constructed a single-cell RNA sequencing (scRNA-seq) database from unilateral ischemia reperfusion injury (uIRI) mouse model and identified five heterogeneous fibroblast subpopulations, with C0-Sema3d^hi fibroblasts significantly increasing post-injury and correlating with reduced endothelial cells. Conditioned medium from Sema3d^hi-NRK49F cells inhibited focal adhesion formation and induced cytoskeletal collapse in human umbilical vein endothelial cells (HUVECs), preventing migration and angiogenesis. Mechanistically, Sema3d^hi fibroblasts secrete Sema3d, activating the endothelial Plexin D1 receptor, leading to Arf6 activation and integrin β1 internalization, thus suppressing endothelial function. Systemic administration of Sema3d-shRNA using adeno-associated virus serotype 9 (AAV9) effectively reduced Sema3d levels and significantly alleviated renal fibrosis in mice. The presence of SEMA3D⁺ fibroblasts was confirmed by analyzing human scRNA-seq data and through immunofluorescence staining of kidney sections from patients with kidney diseases. This study reveals new target for mitigating renal fibrosis and microvascular loss, suggesting that targeting the Sema3d signaling pathway may provide a novel strategy for preventing AKI fibrotic progression.

Estrogen signaling has emerged as a pivotal regulator in the development and progression of various cancers, including those of the urological system. While urological malignancies have traditionally been linked with androgen signaling, recent studies reveal a complex interplay where estrogen receptors-ERα, ERβ, and GPER-modulate critical cellular processes such as proliferation, apoptosis, and metastasis in these cancers. Here we show that estrogen receptors, through both genomic and non-genomic pathways, exert dual roles in either promoting or inhibiting tumor growth, making them both a challenge and a potential therapeutic target. These insights suggest that targeting estrogen receptor pathways could offer novel treatment strategies, especially for advanced or therapy-resistant urological tumors.Furthermore, understanding the molecular mechanisms through which estrogen receptors influence tumor progression could lead to the development of more specific and less toxic treatment options. The findings not only shift the paradigm of estrogen's role in cancer biology but also underscore the potential for personalized treatments, where estrogen receptor status could be used to tailor more effective and individualized therapeutic regimens. This review ushers in new possibilities for advancing urological oncology, where estrogen signaling may hold the key to overcoming current therapeutic challenges and improving clinical outcomes.