International Journal of Biological Sciences最新文献

Immune checkpoint inhibitors have been proven effective for recurrent or metastatic cases of microsatellite instability-high (MSI) endometrial cancer (EC). However, drug resistance exists in a noticeable proportion of patients. Elucidating the underlying mechanisms would help develop new therapeutic strategies and benefit in improving patients' prognosis. Circular RNAs (circRNAs) are excellent biomarkers due to their stability and tissue specificity. Evidence has showed that circRNAs could mediate immune evasion in several types of malignancies. However, whether they regulate the immune response in MSI EC has not been explored. Here, based on the results of our former circRNA array, which identified the differentially-expressed circRNAs in MSI EC, we found that a circRNA, circCLMP, was negatively correlated with CD8⁺ T cell infiltration in MSI EC, and up-regulated in ICI-resistant MSI EC. In vivo assays showed that circCLMP could alter the anti-tumor immunity and promote tumor growth. Mechanistically, circCLMP shielded IRF3 from binding to TBK1, interfered with the phosphorylation and nuclear translocation of IRF3, thereby inhibiting the activation of interferon response, suppressing CD8⁺ T cell infiltration in the tumor environment, and eventually mediating immune evasion and promoting the progression of MSI tumors. Targeted knockdown of circCLMP combined with anti-PD-1 inhibitor treatment effectively enhanced the anti-tumor effects in the preclinical MSI EC PDX model. For the first time, our study reported an immunoregulating circRNA in MSI EC, which may provide insights into developing new biomarkers and therapeutic targets for overcoming immunotherapy resistance in MSI EC.

Rationale: Androgen deprivation therapy (ADT) is the cornerstone of prostate cancer (PCa) treatment. Prolonged ADT inevitably increases the risk of neuroendocrine differentiation, which leads to the development of hormone-refractory subtypes. In this study, we explored the molecular mechanisms underlying the neuroendocrine differentiation of PCa cells under ADT. Methods: We performed digital spatial profiling (DSP) sequencing using tissue microarrays from five patients with PCa who underwent neoadjuvant therapy before radical prostatectomy at the Nanjing Drum Tower Hospital. Results: Glutathione S-transferase alpha 1 (GSTA1) was identified as a driver of neuroendocrine differentiation in PCa cells using DSP sequencing of tissue microarrays prepared from clinical samples. Following enzalutamide (ENZ) treatment, GSTA1 expression is inhibited. Decreased GSTA1 levels have also been reported in patients with neuroendocrine PCa (NEPC). GSTA1 knockdown leads to increased intracellular reactive oxygen species (ROS), which can activate the inflammatory gene, tumor necrosis factor receptor superfamily member 13B (TNFRSF13B). TNFRSF13B induces c-Fos expression, forming a transcriptional complex with c-Jun, thereby regulating chromogranin A (CHGA) and promoting the neuroendocrine phenotype. Conclusion: Our study suggested that GSTA1 deficiency leads to elevated ROS levels and activation of TNFRSF13B and c-FOS, which subsequently transcriptionally regulate CHGA and ultimately drive neuroendocrine differentiation in PCa.

The mechanisms by which circRNAs regulate estrogen receptor (ER)-positive breast progression and therapeutic resistance remain poorly defined. By screening circRNAs involved in ER signaling, circESR1 was identified as a novel circRNA exhibiting high specificity of expression in ER+ breast cancer. CircESR1 interacted with HNRNPAB, which was transcriptionally activated by ER/SP1 signaling. HNRNPAB promoted the back-splicing and expression of circESR1 by binding to the Alu elements of cognate pre-mRNA; and circESR1 transcripts increased the stability and expression of HNRNPAB, ensuring an efficient positive feedback loop as reflected in antiestrogen-resistant breast cancer cells. Furthermore, HNRNPAB interacted and stabilized CDK1 and CDK6 mRNA, which was facilitated by its asymmetrical binding of circESR1, to promote cell cycle progression. Patients whose cancer exhibited high levels of circESR1 and/or HNRNPAB exhibited advanced prognostic stage and poor survival. Combined use of circESR1 ASO and CDK4/6 inhibitors were shown to be an effective therapeutic approach overcoming antiestrogen resistance in breast cancer xenograft models. Hence, these findings elucidated a novel signaling complex centered around circESR1 and HNRNPAB in ER+ breast cancer, and suggested that circESR1 might represent a potential therapeutic target for this disease.

Dietary intervention provides a novel approach for cancer therapy. Elaidic acid (EA), which accounts for 80-90% of total trans fatty acids in foods, has recently been found to exert anti-tumor effects. However, the biological functions and underlying mechanisms of EA remain elusive in hepatocellular carcinoma (HCC). In this study, targeted fatty acid metabolomics demonstrated that among 44 types of fatty acids, the concentration of EA decreased most significantly when comparing plasma from HCC patients with plasma from healthy people. Through in vivo assays using HCC orthotopic and xenograft mouse models, we further revealed that dietary EA attenuates HCC growth. Notably, when gut microbiota was depleted using a cocktail of antibiotics, the anti-tumor effect of EA was diminished, confirming that EA suppresses HCC tumor growth by modulating gut microbiota. Mechanistically, analysis of 16S ribosomal RNA sequencing showed that dietary EA markedly increases the abundance of intestinal Ligilactobacillus murinus (L. murinus). Subsequent untargeted metabolomic sequencing analysis further demonstrated that dietary EA drives the production of L. murinus-derived spermidine (SPD), which attenuates HCC growth in vitro as well as in vivo. The observed impact correlated with the phosphorylation of p38 MAPK and the upregulation of biomarkers pertinent to apoptosis and proliferation, including tumor protein 53, bcl-2-associated X protein, and cysteine-requiring aspartate protease 3. Taken together, our findings highlight the important role of intestinal L. murinus-derived SPD in EA-mediated HCC suppression, thereby offering a promising dietary strategy for HCC treatment.

Photodynamic therapy (PDT) has evolved over the past decade into a versatile cancer treatment modality, fueled by advances in photosensitizer design, nanotechnology, and immunotherapy. Smarter photosensitizers, ranging from activatable and oxygen-independent scaffolds to red/NIR-absorbing chromophores, have expanded tumor selectivity and tissue penetration. Nanocarrier-based delivery systems have improved solubility, biodistribution, and combinatorial theranostic potential, while innovative light sources such as upconversion nanoparticles, implantable LEDs, and X-ray-driven PDT are addressing penetration constraints. Importantly, PDT is no longer confined to local cytotoxicity but is increasingly recognized as an immunomodulatory platform capable of synergizing with immune checkpoint blockade (ICB) and in situ vaccination strategies. However, despite this progress, significant barriers remain, including poor standardization of dosimetry, heterogeneity in tumor hypoxia, unresolved safety concerns regarding nanocarriers, and limited clinical validation of combination regimens. This highlight review critically evaluates these advances and bottlenecks, outlining how PDT can realistically transition from a niche light-based therapy into a central component of precision oncology and next-generation immunotherapy.

Identifying cellular proteins and processes crucial for viral infection is vital for comprehending virus-induced disease mechanisms and developing host-targeted therapies. PRRSV has been shown to take advantage of host metabolic reprogramming and immunosuppression to promote virus production, but the host factors that coordinate these processes have not been fully elucidated. Here, we showed that NUDT7 expression was significantly increased during PRRSV infection by ETS1 targeting its promoter. We also found NUDT7 enhance PRRSV replication by reprograms viral infection-induced intracellular lipid droplets (LDs) synthesis. Mechanistically, NUDT7 interacts with and targets the ubiquitin-ribosomal fusion protein UBA52 for proteasomal degradation. NUDT7 enhances lipid droplet formation and stabilizes the lipogenic transcription factor SREBF1 by blocking UBA52-mediated K11/K27/K48 polyubiquitination. NUDT7-UBA52-SREBF1 axis drives lipid metabolic reprogramming, creating a favorable environment for PRRSV replication. Additionally, NUDT7 inhibits type I interferon signaling and the expression of interferon-stimulated genes, facilitating viral immune evasion. These findings suggest that NUDT7 could be a therapeutic target for combating PRRSV infection, offering a novel perspective and theoretical foundation for developing targeted metabolic-immune antiviral strategies.

Chronic ultraviolet (UV) exposure drives skin degeneration, causing photoaging and increased carcinogenesis risk. To address complex pathogenesis and limited treatments, we developed GS5, a novel anti-photoaging sericin. GS5 fuses natural sericin with Seq10, a Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) protein-protein interaction (PPI) inhibitor identified through molecular docking/dynamics. Seq10 binds Keap1, activates Nrf2 transcription, and alleviates UVA-induced photoaging Nrf2-dependently. Given the application bottlenecks of peptide molecules, we efficiently expressed the GS5 recombinant protein using the silk gland reactor of the silkworm and optimized the enzymatic extraction process to obtain high-activity GS5 sericin. In vitro, GS5 outperformed wild-type (WT) sericin and Seq10, enhancing viability/proliferation in irradiated keratinocytes and fibroblasts while reducing senescence markers (Senescence-associated β-galactosidase (SA-β-gal), P21), reactive oxygen species (ROS), DNA damage, and inflammation. GS5's photoprotection mechanistically requires Nrf2 activation. In vivo, GS5 reversed skin damage in UVA-irradiated mice, improving appearance and histology. RNA-seq implicated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway inhibition via immune/inflammation-related gene modulation. This study innovatively combines a targeted PPI inhibitor with sericin to create GS5, which mitigates photoaging through dual Nrf2 activation and JAK-STAT inhibition, offering a safe, effective, and sustainable therapeutic strategy.

Liver fibrosis is a pathological outcome of chronic liver injury and is primarily driven by the continuous activation of hepatic stellate cells (HSCs). During activation, HSCs depend on aerobic glycolysis to maintain their fibrogenic characteristics, suggesting that metabolic reprogramming could serve as an effective therapeutic approach. In this study, we demonstrate that Curcumol, a natural compound derived from plants in the Zingiberaceae family, selectively removes activated HSCs by interfering with the lactate-KAT8-HK2 regulatory pathway. In HSCs, lactate produced through glycolysis activates the acetyltransferase KAT8, which catalyzes K346 lactylation of hexokinase 2 (HK2). This modification creates a positive feedback mechanism that stabilizes HK2. Curcumol acts directly on KAT8, inhibiting HK2 lactylation and promoting HUWE1-mediated ubiquitination and degradation of HK2. The resulting loss of HK2 removes its inhibitory influence on RIPK1 ubiquitination, leading to activation of the RIPK1/RIPK3/MLKL signaling pathway and triggering necroptosis. In vivo experiments show that Curcumol substantially reduces liver fibrosis, lowers the expression of glycolytic enzymes, and improves liver function in mice with carbon tetrachloride (CCl₄)-induced fibrosis. However, these protective effects are lost when KAT8 is overexpressed. This study highlights HK2 lactylation as a key metabolic control point for HSC survival and identifies Curcumol as a potential anti-fibrotic compound that targets the KAT8-HK2 pathway, linking metabolic inhibition with necroptotic cell death.

Hepatic fibrosis, driven primarily by hepatic stellate cells (HSCs) activation induced by TGF-β, currently lacks effective therapies. In this study, we demonstrated that deficiency of αKlotho, an extrahepatic antiaging protein, due to genetic ablation in kl/kl model or aging caused spontaneous hepatic fibrosis, as evidenced by an increased collagens deposition and TGF-β signaling hyperactivation. KP1, a small peptide derived from human αKlotho protein, recapitulated its anti-fibrotic potential and blocked HSCs activation induced by TGF-β1. Mechanistically, KP1 acted as a competitive TGF-β receptor 2 (TβR2) antagonist, disrupted TGF-β1/TβR2 engagement, and suppressed both canonical and noncanonical TGF-β signaling in HSCs. Infusion of KP1 in vivo rescued hepatic integrity, restored liver function, inhibited TGF-β signaling and mitigated hepatic fibrosis in kl/kl mice. In mouse model of carbon tetrachloride-induced hepatic fibrosis, KP1 exhibited preferential accumulation in injured liver after intravenous injection, disrupted TGF-β1/TβR2 interaction, inhibited HSCs activation, and ameliorated hepatic fibrosis. Similarly, KP1 also mitigated cholestatic fibrosis induced by bile duct ligation. Collectively, these studies establish KP1 as a novel, mechanism-driven therapeutic peptide that potently inhibits HSCs activation and liver fibrogenesis. Its liver-targeted delivery and efficacy across diverse fibrosis models underscore KP1 as a promising next-generation therapeutic remedy for fibrotic liver disease.

Neuroendocrine prostate cancer is an aggressive disease characterized by early metastasis, drug resistance and poor prognosis. Genome-wide association studies (GWAS) previously identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer. SNP rs11067228 as a significant variant associated with castration-resistant metastasis (CM) in prostate cancer (PCa). However, mechanisms underlying activity of the rs11067228 risk variant remain unclear. Here, we demonstrated that risk SNP rs11067228 is located in an H3K27ac-enriched active enhancer, and that activity of that region affects castration-resistance and neuroendocrine differentiation in PCa cells. We identified the RNA-splicing factor SRRM4 as a functional target gene as shown in both cell line and xenograft model. In addition, overexpression of SRRM4 is sufficient to induce PCa cell drug resistance and neuroendocrine differentiation. Moreover, site-directed mutation of the rs11067228 non-risk G to the risk A allele enabled binding of the transcription factor SOX4, activating candidate target gene expression. Taken together, our findings indicated that the rs11067228-associated enhancer modulates expression of SRRM4 via allele-specific long-range chromatin interactions, thereby governing PCa drug resistance and neuroendocrine differentiation.