EMBO Molecular Medicine最新文献

Endemic and emerging viral diseases continue to impose significant health, economic, and societal burdens worldwide. Vaccines and therapeutics represent two key pillars in the fight against these threats. Since the clinical success of mRNA vaccines during the COVID-19 pandemic, mRNA therapeutics have rapidly evolved from a niche innovation into a validated and versatile medical platform. While early efforts focused primarily on vaccine development, recent advances have expanded the scope to antiviral applications of in vitro-transcribed mRNA. Emerging strategies include in vivo expression of neutralizing antibodies for passive immunization, delivery of innate immune effectors such as interferons and antiviral peptides, and programmable CRISPR-based antiviral systems. In parallel, progress in mRNA delivery technologies has enabled clinical translation, although challenges related to stability, specificity, and immunogenicity remain. In this Perspective article, we review recent preclinical and clinical advances in mRNA therapeutics for viral infections. We also highlight key scientific, technical, and regulatory challenges, and propose strategic solutions to address the pressing need for controlling endemic viral diseases and enhancing global pandemic preparedness.

Pretomanid is a unique anti-tuberculosis agent that inhibits both cell-wall synthesis and bioenergetics in Mycobacterium tuberculosis. While targeting the cell wall triggers a rapid bactericidal effect on replicating mycobacteria, the release of nitric oxide is linked to bactericidal potency against antibiotic-tolerant, non-replicating subpopulations through interference with the electron transport chain. Nonetheless, the specific molecular target(s) of the drug remain unknown. Through the utilization of genetic and chemical biology approaches, we present evidence that pretomanid inhibits both the cytochrome bcc:aa₃ and bd oxidase respiratory branches. This property leads to a pronounced synergy with telacebec (Q203), a clinical-stage drug targeting the cytochrome bcc:aa₃, while concurrently curtailing the emergence of resistance to pretomanid. Furthermore, the incorporation of the cytochrome bd oxidase inhibitor ND-011992 resulted in a triple drug combination highly bactericidal against antibiotic-tolerant, non-replicating as well as replicating M. tuberculosis. The combination of pretomanid and drugs targeting the terminal oxidases holds the potential to serve as the cornerstone for an efficacious sterilizing drug regimen against tuberculosis.

Acute rejection (AR) remains a critical challenge to graft survival in kidney transplantation. Although dextrorotatory-amino acids (D-AAs) have been recognized as biologically active compounds, their role in mediating immunosuppression was poorly depicted. To address this, serum samples from renal transplant recipients were analyzed via [d0]/[d5]-estradiol-3-benzoate-17β-chloroformate (17β-EBC) based ion mobility-mass spectrometry (IM-MS) to assess D-AAs levels. scRNA-seq data from the GSE109564 dataset were analyzed. Additionally, murine skin and kidney transplantation models were utilized to assess the in vivo impact of d-kynurenine (D-Kyn) treatment on AR. Through analysis of patient serum and murine transplantation models, we identified D-Kyn as a key metabolite whose elevated levels correlate with stable graft function. We found that D-Kyn, more effectively than its chiral counterpart L-Kyn, inhibits the inflammatory activity of M1 macrophages. This suppression is mediated via the PHGDH/TLR4/Caspase-1 pathway, reducing the transcription and secretion of inflammatory cytokines. In murine models of skin and kidney transplantation, D-Kyn treatment demonstrated potent immunosuppressive effects, attenuating macrophage-mediated inflammation and CD8 + T cell activation, potentially through regulation of macrophage-derived IL-23a. Our findings reveal D-Kyn as a promising therapeutic candidate for preventing acute rejection and improving transplant outcomes and lay the foundation for future clinical applications from the perspective of dextrorotatory amino acids.

A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSC^med (Lin^-, Sca-1⁺, CD49f^med) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSC^med cells isolated from prostate-specific Pten-deficient (Pten^pc-/-) mice, we identify the emergence of castration-resistant LSC^med cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Pten^pc-/- LSC^med characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.

Dysregulation of alternative splicing - mediated by factors such as RBM20 or SLM2 - can affect proper gene isoform control, disrupting gene isoform homeostasis and underpins severe cardiomyopathy in both animal models and patients. Although innovative therapies target various sarcomeric components, the impact of isoform switching in cardiac disease remains poorly understood. Here, we applied nanopore long-read sequencing to map the full-length transcriptome of left ventricular tissue from thirteen nonfailing controls, ten patients with dilated cardiomyopathy (DCM), and ten with ischemic cardiomyopathy (ICM). Our analysis identified 78,520 transcripts, 31% of which represent novel isoforms of known genes. Notably, the transcriptomes of DCM and ICM were largely indistinguishable, indicating that end-stage heart failure is characterized by a convergent isoform landscape, irrespective of disease etiology. Among 11 prototypical sarcomere genes, 10 displayed highly significant isoform shifts (p = 5.23 × 10^-45-2.89 × 10^-200). Focusing on tropomyosin, we observed that while the predominant cardiac gene TPM1 showed moderate up-regulation of its transcript isoforms, transcripts derived from TPM3-typically expressed at lower levels in the healthy heart-were markedly increased in heart failure.