m6A-driven NAT10 translation facilitates fatty acid metabolic rewiring to suppress ferroptosis and promote ovarian tumorigenesis through enhancing ACOT7 mRNA acetylation.

RNA epigenetic modifications have been implicated in cancer progression. However, the interplay between distinct RNA modifications and its role in cancer metabolism remain largely unexplored. Our study demonstrates that N-acetyltransferase 10 (NAT10) is notably upregulated in ovarian cancer (OC), correlating with poor patient prognosis. IGF2BP1 enhances the translation of NAT10 mRNA in an m6A-dependent manner in OC cells. NAT10 drives tumorigenesis by mediating N4-acetylcytidine (ac4C) modification of ACOT7 mRNA, thereby augmenting its stability and translation. This NAT10-ACOT7 axis modulates fatty acid metabolism in cancer cells and promotes tumor progression by suppressing ferroptosis. Additionally, our research identifies fludarabine as a small molecule inhibitor targeting NAT10, inhibits the ac4C modification and expression of ACOT7 mRNA. By using cell derived xenograft model and patient derived organoid model, we show that fludarabine effectively suppresses ovarian tumorigenesis. Overall, our study highlights the pivotal role of the NAT10-ACOT7 axis in the malignant cancer progression, underscoring the potential of targeting NAT10-mediated ac4C modification as a viable therapeutic strategy for this disease.

Anti-tumor effect of PD-L1-targeting antagonistic aptamer-ASO delivery system with dual inhibitory function in immunotherapy.

Checkpoint inhibitor antibody therapy by blocking the interaction of surface programmed death-ligand 1(PD-L1) and programmed cell death protein 1(PD-1) has promising advantages in cancer immunotherapy. However, the response of many patients remains unsatisfactorily, suspected to be relevant to PD-L1 located in other cellular compartments and antibodies do not have access to the intracellular compartments. Herein, we identify a PD-L1-targeting DNA aptamer (PA9-1) with dual roles, including an antagonist and a delivery agent dependent on PD-L1 internalization. And we design the PD-L1-targeting antagonistic aptamer-ASO delivery system (PA9-1-ASO), with synergistic inhibitory PD-L1 activity involving the combination of blockade and silencing mechanisms. This chimera not only blocks PD-L1/PD-1 but also achieves targeted delivery of the conjugated ASO to reduce both surface PD-L1 and total PD-L1 expression. Compared with the single blockade, this chimera with the dual inhibitory function synergistically inhibits PD-L1 to amplify immunotherapeutic efficacy, providing a promising synergistic strategy for immunotherapy.

Efficient Targeted Delivery of Bifunctional Circular Aptamer-ASO Chimera to Suppress the SARS-CoV-2 Proliferation and Inflammation.

Inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and excessive inflammation is the current task in the prevention and treatment of corona vireus disease 2019 (COVID-19). Here, a dual-function circular aptamer-ASO chimera (circSApt-NASO) is designed to suppress SARS-CoV-2 replication and inflammation. The chemically unmodified circSApt-NASO exhibits high serum stability by artificial cyclization. It is also demonstrated that the SApt binding to spike protein enables the chimera to be efficiently delivered into the host cells expressing ACE2 along with the infection of SARS-CoV-2. Among them, the SApt potently inhibits spike-induced inflammation. The NASO targeting to silence N genes not only display robust anti-N-induced inflammatory activity, but also achieve efficient inhibition of SARS-CoV-2 replication. Overall, benefiting from the high stability of the cyclization, antispike aptamer-dependent, and viral infection-mediate targeted delivery, the circSApt-NASO displays robust potential against authentic SARS-CoV-2 and Omicron, providing a promising specific anti-inflammatory and antiproliferative reagent for therapeutic COVID-19.

Multiple antiviral approaches of (-)-epigallocatechin-3-gallate (EGCG) against porcine reproductive and respiratory syndrome virus infection in vitro.

Porcine reproductive and respiratory syndrome virus (PRRSV) remains an economically important pathogen in the global pig industry, effective measures to control the virus are still lacking. (-)-Epigallocatechin-3-gallate (EGCG), the most abundant and bioactive catechin in green tea, has been reported to have antiviral effect against the diverse groups of viruses. In this study, the comprehensive anti-PRRSV activity of EGCG was investigated using various in vitro assays. EGCG effectively inhibited PRRSV infection and replication in porcine alveolar macrophages (PAMs), regardless of whether it was administrated pre- or post-infection, and the cytotoxicity to PAMs was low. Next, anti-PRRSV approaches of EGCG were characterized in MARC-145 cells. EGCG was demonstrated to be able to significantly prevent PRRSV from infecting MARC-145 cells either through blocking of EGCG-treated viruses docking to susceptible cells involving a direct virus-EGCG interaction or by blocking of the infective virus binding to EGCG pre-treated cells via triggering down-regulation of viral receptors and/or related proteins required for infection. In addition, PRRSV replication was suppressed in MARC-145 cells treated with EGCG post-infection, likely because of down-regulation of pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-8. Taken together, these data showed that treatment of primary PAMs with EGCG can inhibit PRRSV infection and revealed that multiple antiviral approaches of EGCG operate in PRRSV-susceptible MARC-145 cells.