METTL5 deficiency induces oligoasthenoteratozoospermia via impaired 18S rRNA mA methylation in humans and mice.

Recent studies have highlighted RNA modifications as integral regulators of gene expression during spermatogenesis. Ribosomal RNAs (rRNAs) are the most abundant RNA in cells, while the function and clinical relevance of rRNA modifications in spermatogenesis remain poorly understood. Here, we identified 4 pathogenic heterozygous variants of METTL5 in 1,427 patients with male infertility characterized as oligoasthenoteratozoospermia (OAT).

PABPN1-C5 axis promotes hepatocellular carcinoma progression via NF-κB activation.

RNA polyadenylation is a key post-transcriptional modification essential for gene expression regulation. However, the role and mechanism of polyadenylation and its key molecule, polyadenylate binding protein nuclear 1 (PABPN1), in hepatocellular carcinoma (HCC) remain poorly understood. This study investigates the role of PABPN1 and its regulatory genes in HCC progression to identify potential therapeutic targets.

N-methylguanosine tRNA modification promotes gastric cancer progression by activating SDHAF4-dependent mitochondrial oxidative phosphorylation.

N-methylguanosine (mG) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of mG tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated mG tRNA modifications in promoting GC progression.

Aberrant METTL1-mediated tRNA mG modification alters B-cell responses in systemic autoimmunity in humans and mice.

Upon activation, naive B cells exit their quiescent state and enter germinal center (GC) responses, a transition accompanied by increased protein synthesis. How protein translation efficiency is adequately adjusted to meet the increased demand requires further investigation. Here, we identify the methyltransferase METTL1 as a translational checkpoint during GC responses.

The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation.

After birth, the heart undergoes a shift in energy metabolism and cytoarchitecture to enhance efficient energy production and cardiac contraction, which is essential for postnatal development and growth. However, the precise mechanisms regulating this process remain elusive. Here we show that the RNA modification enzyme Mettl1 is a critical regulator of postnatal metabolic reprogramming and cardiomyocyte maturation in mice, primarily through its influence on the translation of the rate-limiting ketogenesis enzyme Hmgcs2.

FTO-mediated RNA mA methylation regulates synovial aggression and inflammation in rheumatoid arthritis.

Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (mA) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the mA demethylase fat mass and obesity-associated protein (FTO) in FLS and synovium from RA patients.

NAT10 promotes synovial aggression by increasing the stability and translation of N4-acetylated PTX3 mRNA in rheumatoid arthritis.

Objective: Recent studies indicate that N-acetyltransferase 10 (NAT10)-mediated ac4C modification plays unique roles in tumour metastasis and immune infiltration. This study aimed to uncover the role of NAT10-mediated ac4C in fibroblast-like synoviocytes (FLSs) functions and synovial immune cell infiltration in rheumatoid arthritis (RA).

Methods: FLSs were obtained from active established patients with RA.

CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer.

Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors.

RNA modification-related genes illuminate prognostic signature and mechanism in esophageal squamous cell carcinoma.

Emerging studies have demonstrated the link between RNA modifications and various cancers, while the predictive value and functional mechanisms of RNA modification-related genes (RMGs) in esophageal squamous cell carcinoma (ESCC) remain unclear. Here we established a prognostic signature for ESCC based on five RMGs. The analysis of ESCC clinical samples further verified the prognostic power of the prognostic signature.

RNA modification-mediated mRNA translation regulation in liver cancer: mechanisms and clinical perspectives.

Malignant liver cancer is characterized by rapid tumour progression and a high mortality rate, whereas the molecular mechanisms underlying liver cancer initiation and progression are still poorly understood. The dynamic and reversible RNA modifications have crucial functions in gene expression regulation by modulating RNA processing and mRNA translation. Emerging evidence has revealed that alterations in RNA modifications facilitate the selective translation of oncogenic transcripts and promote the diverse tumorigenic processes of liver cancer.

METTL5-mediated 18S rRNA mA modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression.

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA mA modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (log rank test, p < 0.

ALKBH5-Mediated RNA m A Methylation Regulates the Migration, Invasion, and Proliferation of Rheumatoid Fibroblast-Like Synoviocytes.

Objective: Fibroblast-like synoviocytes (FLSs) are critical for promoting joint damage in rheumatoid arthritis (RA). N -methyladenosine (m A) modification plays key roles in various diseases, but its role in the pathogenesis of RA is largely unknown. Here, we investigate increased demethylase ALKBH5 promotion of proliferation, migration, and invasion of RA FLSs via regulating JARID2 expression.

NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer.

Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCAs) and associated with poor ESCA prognosis. In addition, using ESCA cell lines and mouse models, we confirm the critical functions of NAT10 in promoting ESCA tumorigenesis and progression in vitro and in vivo.

Single-dose injectable nanovaccine-in-hydrogel for robust immunotherapy of large tumors with abscopal effect.

Current cancer immunotherapy [e.g., immune checkpoint blockade (ICB)] only benefits small subsets of patients, largely due to immunosuppressive tumor microenvironment (TME).

METTL1/WDR4-mediated tRNA mG modification and mRNA translation control promote oncogenesis and doxorubicin resistance.

Osteosarcoma is the most common bone tumor that leads to high mortality in adolescents and children. The tRNA N-methylguanosine methyltransferase METTL1 is located in chromosome 12q14.1, a region that is frequently amplified in osteosarcoma patients, while its functions and underlying mechanisms in regulation of osteosarcoma remain unknown.

METTL3-mA-EGFR-axis drives lenvatinib resistance in hepatocellular carcinoma.

Lenvatinib is emerging as the first-line therapeutic option for advanced hepatocellular carcinoma (HCC), but drug resistance remains a major hurdle for its long-term therapy efficiency in clinic. N-methyladenosine (mA) is the most abundant mRNA modification. Here, we aimed to investigate the modulatory effects and underlying mechanisms of mA in lenvatinib resistance in HCC.

Ionizable polymeric nanocarriers for the codelivery of bi-adjuvant and neoantigens in combination tumor immunotherapy.

Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines. Here, we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade (ICB). Current cancer ICB benefits only a small subset of patients, largely due to a lack of pre-existing target cells and checkpoint targets for ICB, tumor antigenic heterogeneity, and tumor immunosuppression.

Emerging functions of tRNA modifications in mRNA translation and diseases.

tRNAs are essential modulators that recognize mRNA codons and bridge amino acids for mRNA translation. The tRNAs are heavily modified, which are essential for forming a complex secondary structure that facilitates codon recognition and mRNA translation. In recent years, studies have identified the regulatory roles of tRNA modifications in mRNA translation networks.

Targeting tumour-intrinsic N-methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy.

Objective: Intrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy.

Design: Tumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs.