International Journal of Biological Sciences最新文献

Clinically, acute kidney injury (AKI) stems from a diverse array of causes including ischemia, exposure to nephrotoxic agents, or sepsis. Renal tubular cells are particularly vulnerable and often sustain the most significant damage during AKI. This raises the question of whether there exists a common pathophysiological mechanism or pathway in renal tubular cells that underlies the development of AKI. We observed that tubular Galectin-3 is significantly up-regulated in four AKI mouse models and its tissue expression shows a positive correlation with tubular injury in human kidneys affected by AKI. The urinary Galectin-3 levels were markedly elevated in a cohort of patients with AKI and these levels correlated with the severity of kidney dysfunction. Based on predictions from bioinformatic analysis and JASPAR database, ChIP-PCR and luciferase-reporter assays demonstrated the direct binding of the transcription factor KLF4 to a specific sequence in the Galectin-3 gene promoter. Furthermore, mice with proximal tubular-specific deletion of KLF4 exhibited reduced kidney injury and inflammation, along with lower Galectin-3 expression in both cisplatin and ischemia-reperfusion-induced AKI. Targeting the KLF4/Galectin-3 axis with Kenpaullone and GB1107 confirmed protective effects against cisplatin-induced cell death and acute kidney injury, respectively. Our study highlights the KLF4/Galectin-3 pathway as a key mediator in the pathogenesis of AKI. Disrupting this signaling pathway may provide a promising therapeutic approach for the treatment of AKI.

Background: Peritoneal metastasis (PM) is a frequent and fatal progression in advanced gastric cancer (GC), shaped by intricate interactions between tumor cells and the tumor microenvironment. Among these, gastric cancer-associated fibroblasts (GCAFs) are key mediators of tumor progression, yet the molecular regulators underlying tumor-stroma crosstalk remain poorly defined. Methods: We combined bulk and single-cell transcriptomics, functional assays, proteomics, and in vivo models to dissect the role of FERMT2 in modulating GC-GCAF interactions and its contribution to peritoneal dissemination. Results: FERMT2 is highly expressed in CAFs and positively correlates with both CAF infiltration and activation in GC. Functionally, FERMT2 maintains the myofibroblastic phenotype of GCAFs by acting as a competing endogenous RNA (ceRNA) for ZEB2, thereby promoting α-SMA transcription. FERMT2 also drives GCAF-derived secretion of transforming growth factor-beta 1 (TGF-β1), which in turn induces FERMT2 expression in GC cells, enhancing their migration, invasion, and resistance to anoikis. In parallel, tumor-derived FERMT2 upregulates COL6A1 and facilitates its transfer to GCAFs via exosomes, amplifying TGF-β signaling and reinforcing CAF activation. Intracellular COL6A1 sustains the pro-metastatic phenotype of GCAFs. Together, these interactions constitute a TGF-β1/FERMT2/COL6A1 positive feedback loop that fuels tumor-stroma crosstalk and promotes peritoneal dissemination in GC. Conclusion: This study identifies a reciprocal regulatory loop involving FERMT2, TGF-β1, and COL6A1, which promotes tumor-stroma interaction and peritoneal dissemination, suggesting a potential therapeutic target for advanced gastric cancer.

Metabolic syndrome (MetS) causes vascular structural abnormalities, nerve damage, hormonal level changes and other lesions, which promote the occurrence and development of erectile dysfunction (ED). Penile vascular endothelial dysfunction is an important pathological feature of MetS-associated ED, and has received increasing attention in recent years. MetS negatively affects penile cavernous vascular function through the synergistic effects of insulin resistance, dyslipidemia, hypertension and obesity. The multiple pathological process may lead to impaired endothelium-dependent vasodilation, progressive fibrosis and reduced penile vascular blood flow reserve. This review summarized several common mechanisms of penile vascular endothelial dysfunction in MetS-associated ED, deeply discussed the roles of common pathological manifestations of MetS such as glucose metabolism disorder, hypertension, dyslipidemia and obesity on penile vascular endothelium, and explored treatments targeting these mechanisms in order to provide potential therapeutic targets and strategies in patients with MetS-associated ED.

Tumor progression locus 2 (TPL2), a member of the MAP3K serine/threonine protein kinase family, is implicated in immune responses and pro-inflammatory protein phosphorylation. Emerging evidence suggests its role in tumorigenesis; however, its contribution to gastric cancer (GC) development remains unclear. Patients' disease progression and tumor tissues obtained were used to perform gene expression and GSEA analysis. Immunohistochemical staining, EMSA, ChIP, immunoprecipitation analyses, confocal microscope image and molecular docking were conducted to investigate the relationship between TPL2 and Peroxisome proliferator-activated receptor delta (PPARδ). Xenograft mouse models were used to study the role of PPARδ/TPL2 axis in tumor growth and the efficacy of blocked TPL2. TPL2 expression was significantly upregulated in GC tissues compared to adjacent normal tissues, and high TPL2 levels correlated with poor patient outcomes. Silencing TPL2 via siRNA or pharmacological inhibition suppressed GC cell proliferation and enhanced sensitivity to doxorubicin (Adriamycin), whereas TPL2 overexpression promoted tumor growth and chemoresistance. Mechanistically, TPL2 activated hypoxia/PPARδ signaling by interacting with PPARδ, thereby enhancing its transcriptional activity. Furthermore, PPARδ transcriptionally upregulated TPL2 expression, establishing a positive feedback loop. Functional studies confirmed the interdependent relationship between TPL2 and PPARδ in regulating GC cell proliferation and drug resistance. This study identifies a novel TPL2/PPARδ positive feedback regulatory loop that drives GC progression and chemoresistance. Targeting this axis may provide new therapeutic strategies not only for GC but also for other diseases associated with pathological hypoxia.

Osteocytes are derived from osteoblasts in the mineralized matrix and are the main source of RANKL required for osteoclastogenesis. We initially found osteocytes as central target cells for Wnt/β-catenin signaling that increases RANKL expression and bone resorption in mice. However, how RANKL is regulated remains unclear. Here, we demonstrated its role and molecular mechanisms using primary osteocytes isolated from long bones. Osteocyte transcriptome sequencing revealed the most associated osteoclast differentiation in KEGG pathways with upregulated expression of Tgfb1/2. In vivo data highlight the specificity of osteocytic Wnt, rather than osteoblastic Wnt, in regulating TGFβ signaling. Activation/inactivation of osteocytic TGFβ signaling stringently promotes/inhibits RANKL expression and osteoclast differentiation in dose- and time-dependent manners. Wnt signaling increases RANKL expression through TGFβ signaling via the physical interaction of its transcription factor Smad4 with the RANKL promoter region. Mice with disrupted TGFβ signaling in osteocytes recapitulate defective osteoclastogenesis and reduced RANKL expression in osteocytes. Thus, osteocytes mediate bone resorption via Wnt-TGFβ signaling axis.

Multiple myeloma (MM) is a prevalent hematologic malignancy with improved survival rates over recent decades, although still uncurable. MM with chromosome 1q Gain (1q+) are clinically and biologically heterogeneous. In this study, we found that NR5A2, located on chromosome 1q and encoding an essential transcriptional regulator of lipid metabolism, has higher mRNA expression in 1q+ patients and could further stratify the prognosis of MM patients. Omics data were analyzed and related experiments were conducted. We demonstrated for the first time that NR5A2 promotes the proliferation and invasion of MM cells by regulating phospholipid metabolism and further inhibit ferroptosis by reducing the related specific substrate in MM cells. Through integrated analysis of the lipid metabolism and proteome, MBOAT1 and MBOAT2 were determined to be the downstream targets of NR5A2. Furthermore, it has been determined that the high expression of NR5A2 is closely related to the resistance of MM cells to dexamethasone (Dexa). Interestingly, we found for the first time that arachidonic acid co-culture with MM cells can promote their sensitivity to Dexa and significantly reverse the resistance to Dexa caused by high expression of NR5A2. These findings provide insights into disease-causing mechanisms and new therapeutic targets for MM patients with 1q+.

While proteasome inhibitors have revolutionized the treatment of hematologic malignancies and significantly improved patient survival, their efficacy in solid tumors remains limited. The recent work by Tang and colleagues demonstrates a novel combination strategy to overcome this limitation. Their study reveals that bortezomib, combined with either tetrathiomolybdate or AMD3100, synergistically kills breast cancer by downregulating expression of the proteasome subunit PSMB5. Crucially, the in vivo antitumor efficacy of these combinations is strictly dependent on an intact immune system, enabling cytotoxic CD8⁺ T cell responses. Although this study raises important mechanistic questions for future investigation, it significantly opens new avenues for expanding the therapeutic application of proteasome inhibitors in solid tumors.

Obesity represents a major global public health challenge. Consequently, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the primary driver of chronic liver disease globally and is currently the most rapidly accelerating factor contributing to hepatocellular carcinoma (HCC). However, current evidence indicates that immunotherapy, a cornerstone of HCC management, yields suboptimal results specifically in MASLD-related HCC (MASLD-HCC) cases. Various immune components constitute a special immune microenvironment in MASLD-HCC, including heterogeneous myeloid cells, lymphocytes and platelets. Furthermore, disruptions in the intestinal barrier, along with the ectopic presence of intestinal flora and metabolites, also influence the immune microenvironment in MASLD-HCC. Elucidating immune cells functions and their interplay with gut microbiota is critical to deciphering MASLD progression to carcinogenesis and immunotherapy resistance. This review synthesizes current insights into the immune microenvironment and gut microbiome in MASLD-HCC, identifies factors influencing the efficacy of immunotherapy, and summarizes potential therapeutic targets to provide detailed guidance for developing effective immunotherapy strategies for MASLD-HCC.

Sec10, as a central component of the eight-protein exocyst complex, plays a crucial role in the exocytosis. However, its role in antiviral immunity has remained elusive. Here, we discover that Sec10 negatively regulates antiviral immune response by downregulation of RIG-I at transcriptional level, thereby facilitating RNA replication in multiple cells. Mechanistically, we demonstrate that ATF4 binds to the RIG-I promoter and promotes RIG-I transcription, and NRF2 upregulates ATF4 activity and expression. Notably, Sec10 triggers the inactivation of the NRF2-ATF4 axis during RNA viral infection, which is, in turn restrains RIG-I transcription, attenuating antiviral IFN-I response. Importantly, Sec10 deficiency results in enhanced innate immunity, diminished SeV load and morbidity in mice. Taken together, we firstly unveil the function of Sec10 in viral infection, and elucidate its novel mechanisms of antiviral immunity via the NRF2-ATF4-RIG-I axis, which provides the potential therapeutic targets and offers new insights for antiviral drug development.