Dihydro-R demonstrates innate immunity against Adenovirus-7 by suppressing the NF-κB/JAK-STAT pathway in a SIRT1-dependent manner.

Severe adenovirus infections pose significant health challenges, particularly in immunocompromised individuals. This study characterizes the antiviral activity of dihydro-resveratrol (Dihydro-R) against adenovirus type 7 and reveals a SIRT1-dependent mechanism. Our study reveals that Dihydro-R effectively inhibits adenoviral replication across multiple cell lines through SIRT1 activation. Mechanistically, Dihydro-R suppresses the NF-κB and JAK/STAT pathways, leading to reduced expression of inflammatory factors. The critical role of SIRT1 in Dihydro-R's antiviral activity was confirmed through reverse validation using a SIRT1 inhibitor. Notably, Dihydro-R's antiviral effects correlate with SIRT1 upregulation, with A549 cells showing the strongest response. Time-course analysis demonstrates maximal inhibition of NF-κB and JAK/STAT pathways within 48 h of Dihydro-R treatment. Furthermore, Dihydro-R modulates the expression of key cytokines, including IL-8, IL-6, and IL-4, contributing to its anti-inflammatory properties. Our findings not only highlight Dihydro-R as a promising therapeutic candidate for adenovirus infections but also provide insights into SIRT1-targeted antiviral strategies. This study opens new avenues for developing natural compound-based therapies against adenoviral infections and potentially other viral diseases involving similar pathways.