Identification of naringenin chalcone as a key gut metabolite for bladder cancer intervention: An integrated strategy combining network pharmacology and molecular dynamics simulation.

BACKGROUND

Bladder cancer (BCa) is a prevalent malignancy with high recurrence. While gut microbiota metabolites influence BCa progression, the specific bioactive components and underlying mechanisms remain elusive. This study integrates network pharmacology and molecular simulations to identify core metabolites and therapeutic targets.

METHODS

We constructed a multidimensional "Microbiota-Substrate-Metabolite-Target" network to screen bioactive candidates. Pharmacokinetics and toxicity were evaluated using SwissADME and ADMETlab. Binding stability was rigorously validated via molecular docking, molecular dynamics (MD) simulations, and MM/PBSA free energy calculations.

RESULTS

Sixty-two pivotal targets were identified, enriched in PI3K-Akt, MAPK, and inflammatory pathways. Naringenin chalcone emerged as the top candidate with favorable safety, uniquely targeting AKT1, NFKB1, and JUN simultaneously. Docking and MD simulations confirmed its robust binding affinity and high structural stability with these core targets.

CONCLUSION

Naringenin chalcone exerts anti-BCa effects by synergistically targeting AKT1, JUN, and NFKB1 to modulate oncogenic and inflammatory signaling. This study identifies a potential lead compound for precision BCa therapy targeting the modulation by gut microbiota.