IKK/NF-κB Inactivation by Salidroside via Targeting TNF-α for the Treatment of LPS-Induced Colitis

Area of Science:

• Pharmacology
• Immunology
• Gastroenterology

Background:

• Tumor necrosis factor-alpha (TNF-α) is a key mediator in inflammatory diseases like inflammatory bowel disease (IBD).
• Targeting TNF-α is a crucial therapeutic strategy for managing IBD.
• Salidroside (Sal) is investigated for its potential anti-inflammatory properties.

Purpose of the Study:

• To investigate the protective effects of salidroside (Sal) against inflammation.
• To explore the molecular mechanisms underlying Sal's anti-inflammatory actions.
• To identify the direct molecular targets of Sal.

Main Methods:

• Network pharmacology was used to predict Sal's targets.
• In vitro (NCM460, RAW264.7 cells) and in vivo (murine colitis model) assays evaluated Sal's anti-inflammatory effects.
• Cellular thermal shift assay (CETSA) and co-immunoprecipitation (Co-IP) confirmed direct target engagement.
• Site-directed mutagenesis and IKK/NF-κB pathway analysis elucidated the mechanism.

Main Results:

• Network pharmacology identified TNF-α as a primary target of Sal.
• Sal significantly reduced inflammation in cellular models and ameliorated colitis in mice.
• CETSA and Co-IP confirmed direct binding of Sal to TNF-α, with specific residues identified.
• Sal inhibited the IKK/NF-κB pathway activation and subsequent pro-inflammatory cytokine production.

Conclusions:

• Salidroside alleviates inflammation by directly binding to TNF-α.
• Sal suppresses the downstream NF-κB signaling cascade.
• Salidroside is a potential therapeutic candidate for TNF-α-driven inflammatory diseases.