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This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site‐specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10‐fold increase in bioavailability and up to a 13‐fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency. A 4‐week oral administration in mdx mice, a model for Duchenne muscular dystrophy (DMD), demonstrates the formulation's unprecedented therapeutic potential, with up to 40% dystrophin expression restoration and 75% recovery of normal fiber functions, surpassing existing treatments and exhibiting substantial long‐term safety. This study presents a potent oral dosage form that dramatically improves UAA incorporation into target proteins in vivo, offering a significant advance in the treatment of nonsense mutation‐mediated disorders and holding considerable promise for clinical translation. [ABSTRACT FROM AUTHOR]

Objective: Manganese ion (Mn2+) is reported to promote the antitumor immune response by activating the cGAS‐STING pathway, but it is unknown whether Mn2+ can prevent the malignant transformation of precancerous lesions. The effects of Mn2+ in treating oral leukoplakia (OLK) were explored in this work. Methods: Peripheral blood Mn analysis of the patients was performed using inductively coupled plasma atomic emission spectroscopy (ICP–AES). A coculture model of dendritic cells (DCs)/macrophages, CD8+ T cells, and dysplastic oral keratinocytes (DOKs) was employed to analyze the role and mechanism of Mn2+ in a simulated OLK immune microenvironment. Western blot, RT–PCR, flow cytometry, enzyme‐linked immunosorbent assay (ELISA), and lactate dehydrogenase (LDH) assays were adopted to detect the mechanism of Mn2+ in this model. 4‐nitroquinoline oxide (4NQO)‐induced OLK mice were used to assess the role of Mn2+ in suppressing OLK progression, and a novel Mn2+‐loaded guanosine‐tannic acid hydrogel (G‐TA@Mn2+ hydrogel) was fabricated and evaluated for its advantages in OLK therapy. Results: The content of Mn in patients' peripheral blood was negatively related to the progression of OLK. Mn2+ promoted the maturation and antigen presentation of DCs and macrophages and enhanced the activation of CD8+ T cells in the coculture model, resulting in effective killing of DOKs. Mechanistic analysis found that Mn2+ enhanced the anti‐OLK immune response by activating the cGAS‐STING pathway. Moreover, Mn2+ suppressed the development of 4NQO–induced carcinogenesis in the mouse model. In addition, the G‐TA@Mn2+ hydrogel had better anti‐OLK effects. Conclusions: Mn2+ enhanced the anti‐OLK immune response by activating the cGAS‐STING pathway, and the G‐TA@Mn2+ hydrogel is a potential novel therapeutic approach for OLK treatment. [ABSTRACT FROM AUTHOR]

Self‐renewal and differentiation of embryonic stem cells (ESCs) are influenced by protein O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) modification, but the underlying mechanism remains incompletely understood. Herein, we report the identification of 979 O‐GlcNAcylated proteins and 1340 modification sites in mouse ESCs (mESCs) by using a chemoproteomics method. In addition to OCT4 and SOX2, the third core pluripotency transcription factor (PTF) NANOG was found to be modified and functionally regulated by O‐GlcNAc. Upon differentiation along the neuronal lineage, the O‐GlcNAc stoichiometry at 123 sites of 83 proteins—several of which were PTFs—was found to decline. Transcriptomic profiling reveals 2456 differentially expressed genes responsive to OGT inhibition during differentiation, of which 901 are target genes of core PTFs. By acting on the core PTF network, suppression of O‐GlcNAcylation upregulates neuron‐related genes, thus contributing to mESC fate determination. [ABSTRACT FROM AUTHOR]

Objective: Proteasome activator 28γ (PA28γ) upregulation plays a critical role in the carcinogenesis of many malignancies, including oral cancer. We aim to screen the related genes of PA28γ and investigate their function in oral mucosa carcinogenesis. Materials and methods: Bioinformatics analysis was performed to screen the related genes of PA28γ. Immunohistochemical analysis was carried out to validate their correlation in oral squamous cell carcinoma (OSCC) and detect their expression levels in the whole process of oral mucosa carcinogenesis. The Kaplan–Meier method was used for estimating the overall survival, and the Cox models were constructed to predict the prognosis. Results: U2 small nuclear RNA auxiliary factor 1 (U2AF1) was screened out, and the correlation between U2AF1 and PA28γ was further validated in OSCC. The expression levels of PA28γ and U2AF1 were gradually increased from normal to oral potentially malignant disorders (OPMD) to OSCC tissues. Overall survival was significantly shorter in patients with high U2AF1 expression and the combined application of U2AF1 and PA28γ notably improved the accuracy of prognosis prediction. Conclusion: U2AF1 and PA28γ might play pivotal roles in the progression of OPMD, which may provide insights into the development of new therapeutic strategies to prevent OPMD from becoming malignant. [ABSTRACT FROM AUTHOR]