Porcine deltacoronavirus (PDCoV), a newly discovered intestinal coronavirus, has rapidly spread among pigs worldwide and has shown the potential for cross-species infection. However, the interaction mechanism between PDCoV and the host’s antiviral response is still poorly understood. In this study, an E3 ubiquitin ligase FBXW8 was explored on PDCoV proliferation. Our findings demonstrate that PDCoV infection increases the expression of FBXW8 through p65-mediated activation of its promoter. We also discovered that FBXW8 suppresses PDCoV replication by directly targeting and inducing the degradation of the PDCoV-encoded nucleocapsid (N) protein. Interestingly, FBXW8 catalyzes the K48-linked polyubiquitination of the PDCoV N protein at a unique lysine-rich region (KR). Furthermore, we observed that the FBXW8-ubiquitinated PDCoV N protein interacts with NDP52, a cargo receptor, leading to autophagic degradation instead of proteasomal degradation. In summary, these findings reveal FBXW8 as a novel host antiviral factor involved in PDCoV infection. It mediates the NDP52-dependent autophagic degradation of the PDCoV N protein. These results provide new insights and a potential target for host defenses against PDCoV.

Human endogenous retroviruses (HERVs), constituting roughly 8% of the human genome, have undergone a profound conceptual evolution from dismissed genomic “fossils” to critical, dualistic regulators in cancer biology. Their pathognomonic reactivation across malignancies orchestrates tumorigenesis through three interconnected molecular axes: (1) genomic destabilization via LTR-mediated insertional mutagenesis, disrupting key loci such as TP53 and MYC ; (2) immune checkpoint subversion, driven by HERV-K envelope glycoprotein-induced PD-L1 upregulation (2.3-fold; p < 0.01); and (3) chronic inflammatory signaling triggered by double-stranded RNA (dsRNA) activation of innate immune pathways (TLR3/MDA5/NLRP3). This foundational mechanistic insight is accelerating clinical translation. Diagnostic advances now feature HERV-K Env-targeted liquid biopsies achieving 92% specificity (AUC = 0.94) for early-stage tumors and artificial intelligence (AI)-enhanced platforms (e.g., DeepHERV, AUC = 0.91) that resolve complex HERV expression landscapes. Therapeutically, an emerging pipeline of strategies is rapidly advancing, from initial first-in-human clinical trials (NCT05687903, NCT05554866) of HERV-directed monoclonal antibodies and vaccines to the highly promising preclinical efficacy demonstrated by HERV-K-specific chimeric antigen receptor (CAR) T-cells (> 70% tumor regression) and locus-precise CRISPR/Cas9 epigenetic silencing. However, clinical translation is complicated by persistent challenges, including intratumoral HERV heterogeneity, a lack of assay standardization (as evidenced by 60% primer discordance), and the fundamental ethical and therapeutic requirement for specificity—that is, precise discrimination between pathogenic HERVs and their essential physiological counterparts. A convergent translational framework—leveraging international consortia for biomarker validation, machine learning for patient stratification, and engineered tumor-selective delivery platforms—is now positioned to harness this novel target class and redefine the next era of precision oncology.