Molecular biomedicine最新文献

Duchenne muscular dystrophy (DMD) is a genetic, progressive neuromuscular disease caused by mutations in the dystrophin protein which compromise the integrity of the sarcolemma. Current care of DMD involves both supportive and targeted disease modifying medications. Obestatin, a peptide derived from preproghrelin, is a potential candidate to enhance existing treatments for DMD. This study was conducted to analyse the molecular mechanism by which obestatin acts on myofiber metabolism and muscle restructuring in DMD. Through human and animal models of DMD, we identify the calcium-activated protein phosphatase 3 (PPP3) as key node in obestatin signalling for restoration of muscle homeostasis and activation of membrane repair. In particular, we describe how obestatin signalling recovers muscle function by coordinated activation of the transcription factor EB (TFEB) and the nuclear factor of activated T cell (NFATc1) in which PPP3 is a core component. TFEB dephosphorylation triggers its nuclear translocation and the activation of macroautophagic/autophagic and mitochondrial biogenesis. NFATc1 promotes the slow myofiber phenotype fibre marker utrophin. Overall, obestatin treatment ameliorates distinctive dystrophic features of DMD, including muscle contractile damage, elevated serum creatine kinase levels, and reduced muscle force. Hence, obestatin represents a promising therapeutic approach for treating DMD, not only as monotherapy but also as part of combinatorial treatment strategies aimed at overcoming the barriers that limit the efficacy of gene or cell therapy.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has significantly increased, prompting the increased use of steatotic donor livers in transplantation, contributing to a higher incidence and severity of ischemia-reperfusion injury (IRI), necessitating the development of targeted interventions for MASLD-related liver transplantation (MASLD-IRI). Here, we identified epithelial membrane protein 1 (EMP1) as a potential diagnostic and therapeutic target in MASLD-IRI using multi-omics analysis and mechanistic investigations in rodent models and cells, further validating our findings in human samples. Phenotypic observations revealed significant activation of hepatic stellate cells (HSCs) under MASLD-IRI conditions, leading to increased inflammatory liver injury, which correlated with significant upregulation of EMP1 in HSC. Mechanistically, EMP1 upregulation inhibited SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1)-mediated ubiquitination and degradation of talin1 (TLN1) by competing with SMURF1 for the TLN1 binding site. The subsequent accumulation of TLN1 further promoted phosphorylation of focal adhesion kinase (FAK), establishing a pro-inflammatory signaling axis-EMP1/TLN1/FAK-that amplified HSC activation and aggravated liver injury. Silencing EMP1 suppressed the TLN1/FAK post-translational modification cascade, thereby attenuating HSC activation and downstream inflammation. These findings highlight the potential of EMP1 as a biomarker to monitor the prognosis of MASLD transplantation, as well as a therapeutic target to improve prognosis.

Multi-omics strategies, integrating genomics, transcriptomics, proteomics, and metabolomics, have revolutionized biomarker discovery and enabled novel applications in personalized oncology. Despite rapid technological developments, a comprehensive synthesis addressing integration strategies, analytical workflows, and translational applications has been lacking. This review presents a comprehensive framework of multi-omics integration, encompassing workflows, analytical techniques, and computational tools for both horizontal and vertical integration strategies, with particular emphasis on machine learning and deep learning approaches for data interpretation. Recent applications of multi-omics have yielded promising biomarker panels at the single-molecule, multi-molecule, and cross-omics levels, supporting cancer diagnosis, prognosis, and therapeutic decision-making. However, major challenges persist, particularly in data heterogeneity, reproducibility, and the clinical validation of biomarkers across diverse patient populations. This review also highlights cutting-edge advances in single-cell multi-omics and spatial multi-omics technologies, which are expanding the scope of biomarker discovery and deepening our understanding of tumor heterogeneity. Finally, we discuss the integral role of multi-omics in personalized oncology, with a particular focus on predicting drug responses and optimizing individualized treatment strategies, supported by real-world clinical practice cases. By bridging technological innovations with translational applications, this review aims to provide a valuable resource for researchers and clinicians, offering insights into both current methodologies and future directions for implementing multi-omics data in biomarker discovery and personalized cancer care.

Colorectal cancer (CRC) is a serious threat to human health, with an approximate 14% mutation rate in the ataxia telangiectasia-mutated (ATM) gene, which is involved in homologous recombination repair. BMN673 (talazoparib), a next-generation poly(ADP-ribose) polymerase (PARP) inhibitor, is the most potent PARP inhibitor (PARPi) reported to date, demonstrating robust anticancer activity. However, the precise mechanism underlying its action in ATM-deficient CRC remains unknown. This study demonstrated that BMN673 stimulated ATM-deficient CRC cell death via a synthetic lethal effect. RNA sequencing analysis revealed significant enrichment of the PERK-ATF4 pathway, mitophagy, and ferroptosis. Functional assays confirmed that BMN673 induced a multifaceted cell death program comprising autophagy-associated death, ferroptosis, and mitophagy, in addition to synthetic lethal. Mechanistically, BMN673 was shown to enhance activating transcription factor 4 (ATF4) transcriptional activity by suppressing poly-ADP-ribosylation (PARylation), facilitating ATF4 binding to the growth differentiation factor 15 (GDF15) promoter region and thereby inducing GDF15 transcriptional expression. Notably, GDF15 overexpression modulated the sensitivity of ATM-deficient CRC cells to BMN673 by promoting autophagy-associated cell death, ferroptosis, and mitophagy, contributing to the anticancer effect of BMN673. Additionally, combining BMN673 with radiotherapy exerted a synergistic anticancer effect on ATM-deficient CRC cells, which was prevented by autophagy inhibition. The findings identified the ATF4-GDF15 pathway as a crucial mediator of BMN673 sensitivity in ATM-deficient CRC cells, revealing therapeutic vulnerability beyond canonical DNA damage repair pathways and providing new insight for combination therapy strategies.

For over 70 years, methotrexate (MTX) has remained a first-line chemotherapeutic agent for acute lymphoblastic leukemia (ALL), playing a pivotal role in maintenance therapy. Understanding the genetic determinants of MTX efficacy is therefore essential for improving clinical outcomes. However, studies on MTX efficacy-related polymorphisms remain limited, particularly for non-coding variants, for which most evidence is based on statistical associations. Here, through integrative bioinformatics analysis and systematic meta-analysis, we identified rs1544105, a non-coding SNP in the folylpoly-γ-glutamate synthetase (FPGS) gene, as closely associated with MTX efficacy. Compared with the GG genotype, the AA genotype increased disease progression risk (OR: 2.23; 95% CI: 1.16-4.30; p = 0.017) and elevated plasma MTX concentration-to-dose ratios at 24 h (WMD: 2.27; 95% CI: 1.04-4.40; p = 0.002) and 40 h (WMC: 0.02; 95% CI: 0.00-0.04; p = 0.033). Using prime editing, we generated homozygous mutant (GG) 293T cells, demonstrating that rs1544105 A > G increased FPGS expression (~ 1.5-fold, p < 0.05) and intracellular MTX retention (p < 0.05). Moreover, both cell-based and animal experiments confirmed that rs1544105 A > G markedly improved MTX efficacy. Mechanistically, dual-luciferase reporter and electrophoretic mobility shift assays revealed that rs1544105 A > G enhanced the binding affinity of the SNP-containing sequence for the transcription factor CREB1, thereby increasing FPGS transcriptional activity and ultimately augmenting MTX efficacy. Our multidimensional study, integrating data analysis with cellular, molecular, and animal experiments, highlights the remarkable regulatory role of a single SNP, rs1544105, in modulating MTX therapeutic response and provides a basis for individualized MTX-based maintenance therapy in ALL patients.

Castration-resistant prostate cancer (CRPC) poses a significant clinical challenge, characterized by limited therapeutic options and unfavorable prognosis, particularly among elderly men. Reactivation of androgen receptor (AR) signaling remains the principal driver of CRPC cell survival and tumor progression even under castrated levels of serum androgen. Lysine methyltransferase 2D (KMT2D) has been established as a key oncogenic driver in prostate cancer, promoting tumor progression via multiple pathways. However, its functional interaction with the AR signaling axis in the context of CRPC remains incompletely understood. In this study, we demonstrate that KMT2D substantially upregulates AR protein levels, thereby reactivating AR signaling under castration conditions. Mechanistically, KMT2D employs its histone methyltransferase function to transcriptionally enhance the expression of G3BP stress granule assembly factor 1 (G3BP1). Upregulated G3BP1 subsequently suppresses the activity of the E3 ubiquitin ligase Speckle Type BTB/POZ protein (SPOP), leading to diminished AR ubiquitination and impaired proteasomal degradation. Furthermore, we explored a novel combination therapy involving the histone methyltransferase inhibitor MI-503 and enzalutamide in AR-positive and AR splice variant-positive cell lines. Our results confirmed the synergistic therapeutic effects of this combination, which can continue to inhibit the AR signaling pathway during the CRPC stage, thereby delaying disease progression. Taken together, our findings elucidate a critical KMT2D/G3BP1/SPOP/AR regulatory axis in prostate cancer progression and propose that targeted inhibition of histone methylation in combination with anti-androgen therapy represents a promising strategy for the management of advanced prostate cancer.

Macrophages are involved in the development of kidney stone disease, and substantial research suggests that macrophage-derived extracellulr vesicles (Mφ-EVs) may play a pivotal role in this process. However, the impact of Mφ-EVs on kidney stone formation and the mechanisms of EVs secretion remain unclear. Here we found that calcium oxalate (CaOx) crystals stimulation leads to increased inflammation and enhanced secretion of extracellular vesicles (EVs) in macrophages. Interestingly, these EVs can be absorbed by renal cells, significantly promoting renal tubular damage and facilitating the formation of CaOx crystals in mouse kidneys. Mechanistically, CaOx crystal stimulation activates endoplasmic reticulum stress (ERS)-related proteins, particularly PKR-like ER kinase (PERK), resulting in the production of EVs containing glucose-regulated protein 94 (GRP94). Concurrently, this process induces lysosomal dysfunction, inhibiting the degradation of EVs by lysosomes and ultimately leading to their release. Knocking down PERK in macrophages could reduce the Mφ-EVs secretion significantly, which decreased in the accumulation of CaOx crystals in the mouse kidneys. Together, our research uncovers a novel mechanism by which CaOx crystal-induced ERS and lysosomal dysfunction in macrophages promote the secretion of EVs, thereby facilitating kidney stone formation. This finding presents a promising therapeutic target for future interventions.

Therapeutic resistance remains a defining challenge in oncology, limiting the durability of current therapies and contributing to disease relapse and poor patient outcomes. This review systematically integrates recent progress in understanding the molecular, cellular, and ecological foundations of drug resistance across chemotherapy, targeted therapy, and immunotherapy. We delineate how genetic alterations, epigenetic reprogramming, post-translational modifications, and non-coding RNA networks cooperate with metabolic reprogramming and tumor microenvironment remodeling to sustain resistant phenotypes. The influence of the microbiome is highlighted as an emerging determinant of therapeutic response through immune modulation and metabolic cross-talk. By summarizing key regulatory circuits, We establishe a unified framework linking clonal evolution, metabolic adaptability, and tumor ecological dynamics. We further synthesizes novel therapeutic strategies that convert resistance mechanisms into therapeutic vulnerabilities, including synthetic lethality approaches, metabolic targeting, and disruption of stem cell and stromal niches. Advances in single-cell and spatial omics, liquid biopsy, and artificial intelligence are emphasized as transformative tools for early detection and real-time prediction of resistance evolution. This review also identifies major translational gaps in preclinical modeling and proposes precision oncology frameworks guided by evolutionary principles. By bridging mechanistic understanding with adaptive clinical design, this work provides an integrated roadmap for overcoming therapeutic resistance and achieving sustained, long-term cancer control.

Cancer is a leading cause of death worldwide. Metabolic reprogramming in cancers plays an important role in tumor initiation, malignant progression and therapeutic response. Based on this, significant progress has been made in the development of the metabolite-based early cancer detection and targeted interventions. Over the past decade, metabolomics has been widely applied to detect metabolic alterations in tumor cells as well as their microenvironment. However, an up-to-date systematic review to summarize the current metabolomic and metabolites in cancer, especially their connections to cancer diagnostics/prognostic biomarkers and therapeutic strategies, is lacking. Here, we first introduced the platforms and analytical processes of metabolomics, as well as their application in different biological matrix of tumor patients. Then, we summarized representative cancer studies in which specific metabolites was found to be act as diagnostic or prognostic/stratification biomarkers. Furthermore, we reviewed the current therapeutic strategies targeting cancer metabolism, particularly the drugs/compounds that are either market-approved or in clinical trials, and also analyzed the potential of metabolites in personalizing precision treatment. Finally, we discussed the key challenges in this field, including the technical limitations of metabolomics and the clinical limitations of therapeutic targeting cancer metabolism, and further explored the future directions such as multi-omics perspective and lifestyle interventions. Taken together, we provides a comprehensive overview from technological platforms of metabolomics to translational applications of metabolites, facilitating the discovery of novel biomarkers and targeting strategies for precision oncology.

Excessive activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome plays a key role in the pathogenesis of various inflammatory diseases. Despite the development of several NLRP3 inhibitors, no specific therapy has been approved for clinical use, underscoring the urgent need for safe and effective agents. Here, we demonstrate that ML345 acts as a highly potent and selective NLRP3 inhibitor with strong therapeutic potential for NLRP3-driven inflammation. ML345 effectively suppresses canonical, noncanonical, and alternative NLRP3 inflammasome activation pathways, without affecting other inflammasomes. Mechanistically, ML345 blocks NLRP3 inflammasome activation independently of its intrinsic insulin-degrading enzyme (IDE) inhibitory activity. ML345 binds to NLRP3 in a non-covalent manner and directly targets tyrosine 381 (Y381), disrupting its essential interaction with NIMA-related kinase 7 (NEK7), consequently preventing inflammasome complex formation. In vivo, ML345 is well tolerated and markedly alleviates inflammatory responses and pathology in mouse models of NLRP3-associated disorders, including systemic inflammation and miscarriage triggered by lipopolysaccharide (LPS). Compared with several previously reported NLRP3 inhibitors, ML345 exhibits superior selectivity and comparable or greater inhibitory potency. These findings establish ML345 as a safe and selective NLRP3 inhibitor with robust anti-inflammasome effects and highlight its potential as a promising therapeutic candidate for NLRP3-driven diseases.