Molecular biomedicine最新文献

Radiation-induced injury remains a significant challenge in the radiotherapy of cancer patients. Ionizing radiation causes various cellular and molecular damages, leading to both acute and chronic organ dysfunction. Its impact extends beyond interrupting standard treatment protocols and adversely affects the quality of life. Therefore, understanding the mechanisms underlying radiation-induced injury and identifying effective treatment strategies are crucial. In this review, we summarize the recent advances in the molecular and cellular mechanisms of radiation-induced injury across various organs and systems, particularly in the lung, gastrointestinal system, brain, skin, and bone. We highlight the roles of oxidative stress, DNA damage response, mitochondrial dysfunction, and epigenetics in radiation pathology, and summarize the relevant signaling pathways and cellular responses involved in radiation damage. Additionally, we discuss the common symptoms, risk factors, and current diagnostic strategies of radiation-induced injuries. Furthermore, this article provides an in-depth review of effective clinical treatments, elucidates their mechanisms of action, and highlights emerging therapeutic approaches, such as stem cell therapy, nanomedicine, and exosome-based interventions, in clinical practice. Despite significant advances in understanding radiation-induced injury, challenges remain in translating molecular insights into effective therapies. The review concludes with a call for integrated, precision medicine-based approaches to better manage radiation-induced injuries and improve patient outcomes.

Inflammatory bowel disease (IBD) is a heterogeneous group of disorders characterized primarily by chronic relapsing intestinal inflammation, encompassing Crohn's disease (CD) and ulcerative colitis (UC), affecting individuals across age groups with variable clinical manifestations. With the advancement of global industrialization, its incidence continues to rise, particularly in newly industrialized regions, which not only severely impairs patients' quality of life but also emerges as a major public health concern threatening digestive system health, accompanied by a substantial healthcare burden, thus necessitating the development of more effective and safer individualized treatment strategies. This review summarizes the pathogenesis of IBD, including intestinal mucosal immune dysregulation, intestinal barrier damage, gut microbiota dysbiosis, reactive oxygen species (ROS) homeostasis imbalance, and the complex crosstalk between genetic and environmental factors; however, clinical treatment still faces numerous challenges: 30%-40% of patients exhibit primary or secondary non-response to existing therapeutic regimens such as biologics and small-molecule drugs, and prolonged administration tends to induce significant side effects. Further integrated herein are emerging strategies such as ROS modulators, novel immune-targeted modulation, intestinal barrier repair agents, microbiota-directed interventions, multi-omics-based precision medicine, and artificial intelligence (AI)-assisted therapy, which represent key directions to address the limitations of traditional treatments. This article begins with an overview of basic pathological mechanisms and offers a comprehensive overview of relevant therapeutic approaches and future development directions, aiming to facilitate the transition of the field from traditional generalized therapies to personalized precision medicine and to bridge the long-standing gap between basic research and clinical practice.

Inflammation resolution is now understood as an active and highly coordinated biological process rather than a passive decline in inflammatory signals. When this program fails, inflammation may become persistent and gradually shift to a chronic pathological state. Such unresolved inflammation is increasingly recognized as a core driver of cardiovascular disease, metabolic disorders, autoimmune pathologies, neurodegeneration, and tumor progression. Although conventional anti-inflammatory drugs can suppress inflammatory mediators, they do not restore immune balance or actively promote resolution, and long-term administration may disrupt host defense and tissue-repair processes. Pro-resolving lipid mediators (PRLMs), including resolvins, maresins, protectins, and lipoxins, represent a distinct class of bioactive metabolites derived from polyunsaturated fatty acids. Recent studies have demonstrated that PRLMs regulate inflammation through specialized pro-resolving programs, such as enhancing efferocytosis, modulating cytokine networks, guiding leukocyte trafficking, and promoting tissue regeneration via receptor-dependent signaling pathways. These findings highlight a conceptual shift in inflammation management from broadly inhibiting inflammation to restoring immune homeostasis. Despite encouraging progress, several challenges hinder clinical translation, including rapid metabolic inactivation, limited delivery strategies, and unresolved pharmacological parameters. In this review, we summarize the current advances in PRLM biosynthesis, signaling pathways, and biological functions across multiple disease contexts. We also discuss emerging therapeutic strategies, biomarker development, and knowledge gaps that require further investigation. PRLM research offers a promising framework for next-generation resolution-based therapeutic interventions.

Cardiac fibrosis following myocardial infarction (MI) is a pivotal driver of ventricular dysfunction and heart failure, yet the molecular checkpoints orchestrating the persistent activation of cardiac fibroblasts remain incompletely defined. Here, we uncover a non-canonical, metabolism-independent function of Uridine-Cytidine Kinase 2 (UCK2) and Uridine-Cytidine Kinase Like-1 (UCKL1) as synergistic regulators of pathological remodeling. We demonstrate that both proteins are robustly upregulated in the border zone of ischemic murine hearts and transforming growth factor-β (TGF-β)-activated human cardiac fibroblasts (HCFs). Mechanistically, UCK2 and UCKL1 physically assemble into an obligate functional complex that acts as a molecular scaffold rather than a metabolic enzyme. This complex recruits the E3 ubiquitin ligase Tripartite Motif Containing 21 (TRIM21) to orchestrate the specific ubiquitination and degradation of the negative regulator SMAD Specific E3 Ubiquitin Protein Ligase 2 (Smurf2), thereby sustaining SMAD Family Member 3 (Smad3) phosphorylation and amplifying fibrogenic TGF-β signaling. Disruption of this axis via combined genetic silencing exerts a synergistic protective effect by abrogating myofibroblast differentiation and extracellular matrix production. Furthermore, therapeutic intervention using adeno-associated virus (AAV)-mediated knockdown of UCK2/UCKL1 significantly attenuates adverse ventricular remodeling, limits scar expansion, and preserves cardiac function in a murine MI model. Collectively, these findings identify the UCK2/UCKL1-TRIM21-Smurf2-Smad3 axis as a novel, druggable signalosome linking kinase "moonlighting" functions to transcriptional reprogramming, offering a transformative therapeutic strategy to arrest the progression of post-ischemic heart failure.

In diabetic skin, even in the absence of infection, the antiviral enzymes 2'-5'-oligoadenylate synthetase (OAS) and ribonuclease L (RNase L) demonstrate abnormally heightened activity. This dysregulation triggers a state of cellular stress, which not only suppresses intracellular protein synthesis but also activates innate immune responses-particularly upon pathogenic bacterial invasion. Whether the sustained activation of the OAS-RNase L pathway in diabetic skin tissue critically contributes to impaired wound healing remains to be determined. We have investigated the pyroptosis changes in human umbilical vein endothelial cells (HUVECs) treated with Lipopolysaccharide (LPS) under high glucose by RNase L small interfering RNA (siRNA) to down-regulate RNase L expression. Under high glucose conditions, we observed abnormal activation of the OAS/RNase L pathway in HUVECs, which further exacerbated cellular pyroptosis upon LPS stimulation. Abnormally activated RNase L, which reduces the expression of methyltransferase 3 (METTL3), led to decreased m⁶A methylation of thioredoxin-interacting protein mRNA (TXNIP mRNA). The decreased degradation of TXNIP mRNA by the hypomethylation leads to increased TXNIP expression, which in turn enhances pyroptosis.. In vitro experiments, the impact of RNase L inhibitor Ellagic acid (EA) on diabetic wound healing in STZ (streptozotocin)-induced diabetic mice was evaluated. We found a reduction in skin pyroptosis and improved wound healing when EA was administered orally. Our results demonstrate that hyperglycemia-induced OAS/RNase L activation increases endothelial cell susceptibility to pyroptosis and inflammatory responses during infection. These findings provide valuable insights for developing novel therapeutic strategies for diabetic wound management.

The receptor for triggering expressed on myeloid cells 2 (Trem2), which is a key hub of immune signals, is a cell-surface receptor expressed selectively in myeloid cells. Macrophages have multi-faceted functions in vascular aging. However, the function of Trem2 and its ligands in vascular aging has not been described. Here, we investigated Trem2's function in aging vasculature using transcriptome analysis, western blotting, and quantitative polymerase chain reaction (qPCR) to assess its expression. Aged (24-month-old) wild-type mice exhibited significantly upregulated Trem2 in aortic senescent macrophages compared to young (2-month-old) controls. Compared with littermate controls, aged mice with macrophage-specific Trem2 knockout (T2-cKO) developed exacerbated arterial stiffness, impaired vascular contractility, and an acceleration of histological aging markers. Trem2 deficiency intensified aortic inflammatory responses and oxidative stress. Mechanistically, interleukin (IL)-13 from senescent macrophages directly bound Trem2, activating the Syk-Sp1-SLC25A51 pathway to enhance mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ transport. This triggered metabolic reprogramming, increasing alpha-ketoglutarate (α-KG) production, which modulated vascular smooth muscle cell (VSMC) phenotype. Notably, α-KG supplementation in vivo rescued Trem2 deficiency-driven vascular aging and dysfunction. Our study identifies the IL-13/Trem2 axis as a protective mechanism against vascular aging via α-KG-dependent metabolic crosstalk between macrophages and VSMCs. Thus, Trem2 may be a treatment target for diseases related to vascular aging.

Poly (ADP-ribose) polymerases (PARPs) are a diverse family of enzymes that regulate genome stability, cell death, and stress responses through ADP-ribosylation. Among them, PARP1, PARP2, and PARP3 are central to cellular DNA repair, while tankyrases, and their isoforms, contribute to telomere maintenance, transcriptional regulation, immune signaling, and metabolism. Dysregulated PARP activity drives genomic instability, apoptosis, parthanatos, and tumor microenvironment remodeling, thereby linking PARPs to oncogenesis, immune escape, and therapy resistance. Clinically, PARP inhibitors (PARPi), such as olaparib, niraparib, rucaparib, and talazoparib, exploit synthetic lethality in homologous recombination-deficient tumors and are increasingly applied in ovarian, breast, prostate, and pancreatic cancers. Beyond oncology, preclinical studies demonstrate antiviral efficacy of PARPi against hepatitis B virus, human immunodeficiency virus, and coronaviruses, and also therapeutic potential in neurodegeneration, cardiovascular disease, fibrosis, and metabolic disorders. However, PARPi resistance arises through restoration of DNA repair, replication fork protection, epigenetic changes, and drug-target dynamics, while adverse events-including hematologic toxicity, gastrointestinal disturbance, and organ-specific effects-limit a broader use. Next-generation PARPi with improved isoform selectivity, PROteolysis-TArgeting Chimera (PROTAC) degraders, and rational combinations with ATR/CHK1 inhibitors, immune checkpoint blockade, or epigenetic modulators offer strategies to enhance efficacy and overcome resistance. Emerging biomarker-driven approaches, including liquid biopsies and functional assays, may further personalize therapy. By integrating canonical DNA repair roles with non-canonical signaling and host-virus interactions, PARPs represent pivotal regulators. Similarly, the versatile therapeutics of PARPi have implications that extend beyond oncology into a broader and diverse range of other human diseases.

Impaired sperm motility is a leading cause of male infertility. Studies indicated that FK506, an immunosuppressive drug, resulted in male mouse infertility or an overall decline in the fertilization capacity of male renal transplant recipients. However, the underlying mechanism is not fully elucidated. Here, we reported that the disruption of FK506 binding protein 12.6 (FKBP12.6) significantly alleviated FK506-induced male infertility in mice by restoring sperm motility and mitochondrial functions in immature sperm. Mechanically, we identified that the FK506-FKBP12.6 complex preferentially bound to the sperm-specific calcineurin, which is composed of a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We revealed that FKBP12.6 deficiency reversed FK506-induced the elevated expression of Down syndrome critical region 1.1 (DSCR1.1, a calcineurin inhibitor) and the reduced expressions of PPP3CC and PPP3R2 in immature sperm. Additionally, we observed that FKBP12.6 deficiency remarkably improved FK506-induced the abnormality of Ca²⁺ release through restoring calcineurin-mediated dephosphorylation at S2808 and S2814 of RyR2, and maintained the mitochondrial homeostasis by suppressing the hyperphosphorylation at S637 of the mitochondrial dynamin-related protein 1 (Drp1) in immature sperm. Furthermore, we demonstrated that FKBP12.6 deficiency reversed FK506-induced the reduction of the acrosome reaction in sperm by retaining the expression of synaptosome-associated protein of 25 kDa (Snap25) in immature sperm, which is essential for the maturation of acrosome exocytosis function. Certainly, our findings should provide an insight in elucidating the mechanism of FK506-induced male infertility, suggesting that FKBP12.6 might be a potential target for male infertility clinically.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, underscoring the need for deeper insights into its molecular mechanisms. The SRY-box transcription factor 9 (SOX9) is a well-characterized oncoprotein critical for the pathogenesis and progression of multiple cancers, including NSCLC. However, the post-translational mechanisms governing SOX9 stability, particularly those mediated by arginine methyltransferases, are poorly defined. In this study, we identify protein arginine methyltransferase 7 (PRMT7) as a novel regulator of SOX9. We demonstrate that PRMT7 directly interacts with SOX9 and enhances its stability in a methyltransferase-dependent manner. Mechanistic investigations reveal that PRMT7 catalyzes mono-methylation of SOX9 at the arginine 160 (R160) residue, which in turn antagonizes SOX9 ubiquitination and subsequent proteasomal degradation mediated by the E3 ligases F-Box and WD repeat domain containing 7 (FBXW7) and kelch like ECH associated protein 1 (KEAP1). Functional assays revealed that PRMT7 promotes NSCLC cell proliferation in vitro and tumorigenesis in vivo in a SOX9-dependent manner. Consistent with these findings, clinical analysis revealed significant co-upregulation of both PRMT7 and SOX9 in NSCLC specimens relative to adjacent normal tissues, with elevated levels of either protein correlating with diminished patient survival. Collectively, our findings establish PRMT7 as a key regulator of SOX9 stability and function, thereby highlighting the PRMT7-SOX9 axis as a promising therapeutic target in NSCLC.

Radioresistance constitutes a major therapeutic barrier in glioblastoma (GBM), frequently leading to tumor recurrence and poor clinical outcomes. Despite advances in multimodal therapies, the molecular mechanisms underlying this resistance remain incompletely understood, limiting the development of effective interventions. This study identifies Fos-like antigen 1 (FOSL1) as a key driver of therapy resistance, with its elevated expression linked to poor prognosis in recurrent GBM. Functionally, FOSL1 knockdown sensitizes GBM cells to irradiation, impairs DNA damage repair, and reduces cell invasiveness. Mechanistically, FOSL1 physically interacts with and stabilizes Protein Arginine Methyltransferase 1 (PRMT1). This interaction enhances PRMT1-mediated asymmetric dimethylation of histone H4 (H4R3me2a) and facilitates methylation of Poly(A) Binding Protein Nuclear 1 (PABPN1). PRMT1, in turn, transcriptionally upregulates Calcyphosine (CAPS), which is essential for the pro-resistance and pro-invasive functions of this axis. We further demonstrate that the FOSL1-PRMT1-CAPS axis concurrently activates both Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ) repair pathways to promote therapeutic resistance. In an orthotopic GBM mouse model, genetic or pharmacological disruption of this axis significantly enhances radiosensitivity and suppresses tumor invasion. Collectively, these findings unveil a previously unrecognized signaling pathway that coordinately regulates DNA repair fidelity and invasive potential in GBM. Our work proposes the FOSL1‑PRMT1‑CAPS axis as a promising therapeutic target for overcoming radioresistance and improving treatment outcomes in GBM patients.