International Journal of Biological Sciences最新文献

Dietary components or patterns have been shown to affect male fertility. The increasing intake of processed foods rich in advanced glycation end products (AGEs) may threaten spermatogenesis. However, the key cell type affected by AGEs in spermatogenic microenvironment remains unspecified. Furthermore, given that subcellular organelle interactions, particularly communications between mitochondria and endoplasmic reticulum (ER), are of paramount importance in male fertility, it is worthwhile to investigate dynamic changes of mitochondria-ER contacts (MERCs) in AGE-driven spermatogenesis dysfunction. In this study, we found that serum AGEs levels increased in patients with oligoasthenozoospermia (OAZ), which was accompanied by decreased inhibin B levels, leading us to explore the effect of AGEs on Sertoli cells. In vivo experiments revealed that AGEs-rich diet disrupted spermatogenesis and induced Sertoli cell senescence and dysfunction in mice. We further confirmed that AGEs elicited an increase in MERCs, as well as ER stress and mitochondrial dysfunction in Sertoli cells. Omega-3 polyunsaturated fatty acids (omega-3), which are a category of dietary supplements with the potential to improve male fertility, were employed in the rescue experiment. We demonstrated that omega-3 mitigate dietary AGE-induced Sertoli cell senescence and OAZ via the remodeling of MERCs, highlighting the AGE-RAGE axis as a potential target for treating male infertility.

Insulin resistance (IR) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) are key drivers of hepatocellular carcinoma (HCC), yet the mechanisms underlying their induction of an immunosuppressive tumor microenvironment (TME) require elucidation. This review posits that the PI3K/Akt/mTOR signaling pathway acts as the central integrator of this process, becoming fundamentally rewired-or "imprinted"-by the unique pathological context of IR/MASH-HCC. We highlight how this "imprinted" pathway integrates disparate pathological signals to precisely direct tumor metabolic reprogramming, TME immune landscape remodeling, and the metabolic-dependent regulation of immune cells. We particularly dissect the synergistic amplification of pathway-mediated immune evasion (including PD-L1 upregulation and EMT) by the IR/MASH microenvironment. This integrated framework, which conceptualizes the pathway as the central processing unit of a uniquely aggressive immuno-metabolic phenotype, not only illuminates the unique biology of IR/MASH-HCC but also provides new insights and a theoretical basis for the clinical translation of targeting the PI3K/Akt/mTOR pathway-encompassing novel combination strategies and biomarker development-to foster more effective clinical interventions.

Chemoresistance remains an obstacle to effective cancer therapy across multiple tumor types. Damaged DNA-binding protein 2 (DDB2), a key component of the nucleotide excision repair (NER) pathway, contributes to chemoresistance by enhancing DNA repair and inhibiting apoptosis. Although the role of DDB2 in tumor progression is context-dependent, its upregulation has been associated with poor prognosis in various malignancies. In this study, elevated DDB2 levels found in breast, liver, cholangiocarcinoma, and lung cancers correlated with reduced patient survival. DDB2 confers resistance to chemotherapeutic agents. Through structure-based virtual screening and molecular dynamics simulations, lapatinib, an FDA-approved EGFR/HER2 inhibitor, was identified as a compound capable of disrupting the DDB2/DNA complex, which was confirmed by the cellular thermal shift assay and chromatin fractionation. Mechanistically, lapatinib binds to the DNA-binding region of DDB2, thereby reducing its chromatin association and promoting proteasomal degradation. Co-treatment with lapatinib and doxorubicin exhibited synergistic cytotoxicity in both cancer cell lines and patient-derived organoids. These findings reveal a previously unrecognized role for lapatinib in targeting DNA repair machinery, supporting its repurposing as a chemosensitizing agent. Our study highlights DDB2 as a critical mediator of chemoresistance and proposes disruption of DDB2-dependent DNA repair as a novel strategy for chemosensitization.

Retinoblastoma (RB) represents the most common primary intraocular malignancy in children, driving a critical need for innovative, targeted therapies that enhance tumor control while preserving vision. Current chemotherapy regimens, such as melphalan, can result in significant systemic toxicity and ocular side effects, underscoring the urgency for safer, more selective treatments. Here, we comprehensively report the design and evaluation of a prion-like self-assembling peptide prodrug (Pri-MP) that exploits the elevated macropinocytic uptake in RB cells to deliver an HDMX-targeting peptide, thereby restoring p53 function. Using single-cell RNA sequencing, we identified a key role for Rac1-PAK1 signaling in driving RB-specific macropinocytosis, which facilitated selective intracellular accumulation of Pri-MP through Au(I)-mediated reversible assembly. This strategy enabled potent p53-dependent apoptosis, prompting marked cell cycle arrest and robust tumor suppression in vitro. In an orthotopic mouse model, intravitreal Pri-MP significantly curtailed tumor burden and demonstrated the potential for enhanced antitumor activity when combined with melphalan, without imposing systemic toxicity or injuring healthy ocular structures. Mechanistically, Pri-MP antagonizes HDMX, lifting its inhibition of p53 and triggering pro-apoptotic transcriptional programs. By leveraging prion-inspired delivery to achieve high specificity and enhanced safety, this approach addresses a longstanding challenge in RB therapy, where efficient tumor targeting remains paramount and vision preservation is essential. Our in vivo findings further confirm the transformative potential of this platform for tumor-specific p53 reactivation, potentially applicable to other neuroectodermal malignancies. Pri-MP thus holds promise as a next-generation modality for eye-preserving RB treatment, meriting further investigation in clinical settings to advance safer, more effective management of this devastating pediatric cancer.

TGF-β/Smad3 signaling is a key pathway leading to the cell death and renal fibrosis. Here we report a new mechanism through which Smad3 mediates renal fibrosis by downregulating the glutathione peroxidase 4 (GPX4), a central inhibitor for ferroptosis. In patients with chronic kidney disease (CKD) and a mouse model of unilateral ureteral obstruction (UUO), progressive renal fibrosis was associated with the overactive Smad3 signaling and the development of ferroptosis identified by decreased GPX4 while increasing two ferroptosis biomarkers including the Transferrin receptor 1 (TFR1) and 4-Hydroxynonenal (4-HNE). Mechanistically, we uncovered that Smad3 could bind directly to GPX4 to repress its transcription while increasing TFR1 and 4-HNE expression, which was abolished when this binding site was mutated. This novel finding was functionally confirmed in the UUO mice and mouse embryonic fibroblasts (MEFs) in which deletion of Smad3 protected against UUO and transforming growth factor-β1 (TGF-β1)-induced loss of GPX4, upregulation of TFR1 and 4-HNE, and progressive renal fibrosis in vivo and in vitro. Importantly, we also found that GPX4 was a downstream target gene of Smad3 and functioned to protect against Smad3-mediated renal fibrosis as silencing GPX4 restored UUO-induced severe renal fibrosis in Smad3 KO mice and in TGF-β1-stimulated Smad3 KO MEFs and SIS3-treated HK-2 cells. Thus, GPX4 is protective in renal fibrosis. Smad3 mediates renal fibrosis via a mechanism associated with GPX4-dependent ferroptosis. The protective effect of GPX4 on Smad3-mediated renal pathologies suggests that targeting the Smad3/GPX4 axis may be a novel therapy for CKD.

Arginine methylation, a critical epigenetic modification, plays a vital role in tumor initiation and progression; however, the mechanism by which arginine methylation regulates tumor recurrence remains unclear. Here, we found the differential changes between arginine methyltransferase PRMT1 and PRMT5 in small cell lung cancer (SCLC) cells after cisplatin and etoposide treatment. PRMT5 increased at the early stage and then decreased at the later stage, while PRMT1 first decreased and then increased, which was regulated by an inflammation activated E3 ubiquitin ligase PELI1. Both PRMT5 and PRMT1 could modify the same substrate CRIP1. At the early stage, PRMT5-mediated CRIP1 R26/68 methylation activated the Wnt/β-catenin pathway to facilitate the acquisition of a stemness phenotype in senescent cells. At the later stage, PRMT1-mediated CRIP1 R16 methylation accelerated the proliferation of stem-like cells by suppressing the p38 pathway, thereby driving rapid recurrence of SCLC post-chemotherapy. Notably, combination therapy using PRMT5 inhibitor GSK3326595 along with cisplatin and etoposide significantly delayed the recurrence of SCLC. Our findings reveal the promoting effect of post-chemotherapy inflammation on tumor recurrence from an epigenetic perspective and provide a potential therapeutic strategy for SCLC treatment.

Severe acute pancreatitis (SAP) is characterized by biphasic systemic inflammation, progressing from initial pro-inflammatory systemic inflammatory response syndrome (SIRS) to subsequent immunosuppressive compensatory anti-inflammatory response syndrome (CARS), which increases infection risks and predicts poor prognosis. Using a pancreatic duct ligation and caerulein-induced SAP murine model, we demonstrate that macrophage extracellular traps (METs) play a pivotal role in immune regulation. Mechanistically, acinar cell activation of the cGAS-STING pathway triggers pyroptosis-mediated IL-33 release. METs subsequently process IL-33 into highly bioactive isoforms through METs-derived proteases (including MMP-12), thereby initiating ST2 receptor-mediated type-2 immune responses. Clinical validation revealed elevated serum METs marker and IL-33 levels in SAP patients. Therapeutic interventions with DNase I and Cl-amidine significantly attenuated IL-33 release, Th2 cell activation, and disease severity in experimental models. Our findings establish METs as critical regulators of SAP-associated CARS and propose METs inhibition as a promising therapeutic strategy for SAP management.

Macrophage is educated by the tubule epithelial cell with maladaptive repair during the renal maladaptive repair, which is one of the most important characteristic features in acute kidney injury (AKI) to chronic kidney disease (CKD) transition. However, the underlying mechanism of orchestrating characterization of macrophage in renal maladaptive repair remains largely unclear. Accordingly, we found that pro-inflammatory macrophage educated by tubule epithelial cell with maladaptive repair was the primary contributor to the renal maladaptive repair in AKI to CKD transition, because macrophages depletion significantly attenuated tubulointerstitial fibrosis. Meanwhile, we found that glycolysis was essential for maintaining pro-inflammatory macrophage phenotype. Further, we demonstrated that HIF-1α played a crucial role in macrophage glycolysis as myeloid HIF-1α knockout alleviated tubulointerstitial fibrosis and AKI to CKD transition in vivo. Mechanistically, NF-κB directly binds to the HIF-1α promoter, boosting its transcription and significantly contributing to tubulointerstitial fibrosis in the AKI to CKD transition. Blockage of NF-κB ameliorated the CKD progression following AKI in vivo. Taken together, our studies provide a novel paradigm in which pro-inflammatory macrophage orchestrates renal maladaptive repair, contributing to the AKI to CKD transition. Blockade of NF-κB-HIF-1 signaling-mediated macrophage metabolic reprogramming may provide attractive strategy for pharmacologic therapy of the AKI to CKD transition.

We tested how the coordination between cyclin D1/cyclin-dependent kinase (CDK) and the cellular prion protein (PrP^C) activates mitogenic/cell proliferation signaling to improve neurological outcomes in acute ischemic stroke (AIS) rats. Compared with those in adipose-derived mesenchymal stem cells (ADMSCs) and the N2a cell line, the cell viability, cell proliferation, cell-stress signaling, and wound healing rates were significantly increased upon overexpression of PrP^C (PrP^C-OE) in ADMSCs (all P<0.001). The cell viability, proliferation. mitochondrial mass, and protein expression of mitogenic signaling markers (cyclin D1, cyclin E1, CDK2, and CDK4) were significantly increased upon PrP^C-OE in ADMSCs compared to ADMSCs that were subjected to a significant reversal of PrP^C-OE by treatment with promazine (a PrP^C formation inhibitor) (all P<0.001). After 3 h of serum-free/hypoxic conditions, the protein expression levels of cyclin D1/CDK, p-Akt and mitogenic signaling markers were significantly increased upon PrP^C-OE in ADMSCs compared with ADMSCs that were treated with palbociclib (a cyclin D1/CDK inhibitor). Adult male Sprague-Dawley rats (n=40) were grouped into Groups 1 (AC), 2 (AIS), 3 (AIS + ADMSCs), and 4 (AIS + ADMSCs with PrP^C-OE). By Day 28 after AIS induction, the neurological function and numbers of NeuN+ cells and myelin basic protein (MBP)+ cells were lowest in Group 2, highest in Group 1 and significantly increased in Group 4 compared with Group 3, whereas the cellular levels of fibrosis and inflammation markers and protein levels of markers of apoptosis, mitochondrial and DNA damage and autophagy exhibited the opposite pattern to neurological function, and protein expression levels of cell-stress signaling proteins (PI3K, Akt, and m-TOR) and PrP^C progressively increased from Groups 1 to 4 (all P<0.0001). In conclusion, activated cyclin D1/CDK coordinated with PrP^C to improve neurological function in the AIS setting.

Endometriosis is a prevalent gynaecological disorder characterized by estrogen-dependent lesions. Pain-particularly dysmenorrhea, chronic pelvic pain, and dyspareunia-is the hallmark symptom of endometriosis. While pain mechanisms remain poorly understood, mast cells are now recognized as central mediators of estrogen-induced pain sensitization. Estrogen drives lesion growth and directly activates mast cells within lesions. Upon activation, mast cells release specific mediators, such as histamine and fibroblast growth factor 2 (FGF2), which enhance peripheral pain signalling and drive central sensitization through elevated responsiveness of dorsal horn neurons and increased neurotransmitter release in the spinal dorsal horn. This complex neuroimmune interaction between mast cells and nerve fibres in endometriotic lesions forms a positive feedback loop that amplifies pain. Targeting mast cells and their specific mediators represents a novel therapeutic strategy for pain management, particularly in cases of refractory pain. Further research into mast cell-mediated mechanisms will enable personalized and targeted therapies, revolutionize care and improve the quality of life for patients with endometriosis.