Curcuminoids amplify host innate antiviral immunity via the CRYAB‐RBM26 axis in viral infection

Abstract Curcuminoids, including curcumin (CUR) and demethoxycurcumin (DMC), are known for their antiviral properties, but their underlying antiviral targets remain unclear, and the relationship between curcuminoids and the type I interferon (IFN‐I) signaling pathway has not been fully elucidated. Here, we explored the regulatory effects of DMC and CUR on the IFN‐I pathway in an EV‐D68‐infected murine model and employed multiomics analysis to identify key drug targets and their interaction networks. FTIR analysis indicated that DMC has better physicochemical stability than CUR, exhibiting greater stability under changes in light, temperature, and pH. In both in vitro and neonatal mouse models, DMC and CUR effectively inhibited EV‐D68 replication by suppressing viral 2A gene expression and the release of proinflammatory cytokines. Both compounds upregulated the molecular chaperone CRYAB (αB‐crystallin), which translocates to the nucleus and acts as a central regulator of host metabolism and antiviral immunity during EV‐D68 infection. Further multiomics analyses revealed that CRYAB overexpression inhibited purine metabolism and upregulated interferon‐stimulated genes. Proteomic profiling identified RBM26 as a key CRYAB‐interacting target. CRYAB stabilizes RBM26 by inhibiting virus‐induced ubiquitination, which leads to enhanced IFN‐I responses. DMC and CUR activated the mtDNA‐cGAS‐STING pathway via RBM26, stimulating downstream signaling and antiviral effects. RBM26 reconstitution altered the splicing of cytidine/uridine monophosphate kinase 2 ( CMPK2 ), resulting in increased nucleotide turnover and reduced cytidine levels, impairing viral replication. DMC/CUR treatment or CRYAB overexpression similarly reduced intracellular cytidine and uridine levels, increasing antiviral activity. Additionally, DMC/CUR restored mtDNA levels suppressed by EV‐D68 infection in an RBM26‐dependent manner, stimulating cGAS‐mediated cGAMP production and activating the STING‐TBK1‐IRF3 axis. These findings not only clarify the molecular mechanisms underlying the antiviral effects of curcuminoids but also highlight their therapeutic potential as host‐directed antiviral agents.