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Abstract Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.

Abstract Epstein‐Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV‐associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA‐based therapeutic vaccines that express the T‐cell‐epitope‐rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc‐LMP2A), truncated EBV nuclear antigen 1 (Trunc‐EBNA1), and Trunc‐EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor‐bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc‐LMP2A, Trunc‐EBNA1, and Trunc‐EBNA3A, are more effective than full‐length antigens in activating antigen‐specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA‐based therapeutic vaccines targeting the T‐cell‐epitope‐rich domain of EBV latent proteins and providing new treatment options for EBV‐associated cancers.

Abstract Nasopharyngeal carcinoma (NPC) is a squamous carcinoma with apparent geographical and racial distribution, mostly prevalent in East and Southeast Asia, particularly concentrated in southern China. The epidemiological trend over the past decades has suggested a substantial reduction in the incidence rate and mortality rate due to NPC. These results may reflect changes in lifestyle and environment, and more importantly, a deeper comprehension of the pathogenic mechanism of NPC, leading to much progress in the preventing, screening, and treating for this cancer. Herein, we present the recent advances on the key signal pathways involved in pathogenesis of NPC, the mechanism of Epstein‐Barr virus (EBV) entry into the cell, and the progress of EBV vaccine and screening biomarkers. We will also discuss in depth the development of various therapeutic approaches including radiotherapy, chemotherapy, surgery, targeted therapy, and immunotherapy. These research advancements have led to a new era of precision medicine in NPC.

Background: The effects of enterolignans, e.g., enterodiol (END) and particularly its oxidation product, enterolactone (ENL), on prevention of hormone-dependent diseases, such as osteoporosis, cardiovascular diseases, hyperlipemia, breast cancer, colon cancer, prostate cancer and menopausal syndrome, have attracted much attention. To date, the main way to obtain END and ENL is chemical synthesis, which is expensive and inevitably leads to environmental pollution. To explore a more economic and eco-friendly production method, we explored biotransformation of enterolignans from precursors contained in defatted flaxseeds by human intestinal bacteria. Results: We cultured fecal specimens from healthy young adults in media containing defatted flaxseeds and detected END from the culture supernatant. Following selection through successive subcultures of the fecal microbiota with defatted flaxseeds as the only carbon source, we obtained a bacterial consortium, designated as END-49, which contained the smallest number of bacterial types still capable of metabolizing defatted flaxseeds to produce END. Based on analysis with pulsed field gel electrophoresis, END-49 was found to consist of five genomically distinct bacterial lineages, designated Group I-V, with Group I strains dominating the culture. None of the individual Group I-V strains produced END, demonstrating that the biotransformation of substrates in defatted flaxseeds into END is a joint work by different members of the END-49 bacterial consortium. Interestingly, Group I strains produced secoisolariciresinol, an important intermediate of END production; 16S rRNA analysis of one Group I strain established its close relatedness with Klebsiella. Genomic analysis is under way to identify all members in END-49 involved in the biotransformation and the actual pathway leading to END-production. Conclusion: Biotransformation is a very economic, efficient and environmentally friendly way of mass-producing enterodiol from defatted flaxseeds. [ABSTRACT FROM AUTHOR]