Exploring the Mechanism of Nicotine on Human Chronic Wounds Based on Network Toxicology and Molecular Docking

Abstract

Background

Chronic wounds represent a pathological state characterized by failure to heal within the normal timeframe, often accompanied by infection, high recurrence rates, and treatment challenges. Nicotine, the primary component of both electronic cigarettes and traditional tobacco, is known not only for its addictive properties but also for its potential to interfere with wound healing through multiple mechanisms. However, its toxicological mechanisms at the multi-target and multi-pathway levels remain unclear.

Methods

This study employed network toxicology and molecular docking techniques. Targets of nicotine and chronic wound-related genes were obtained from databases such as PubChem, GeneCards, and OMIM. Common targets were screened, and a protein-protein interaction (PPI) network was constructed. The CytoHubba plugin was used to identify core targets, while GO and KEGG enrichment analyses were performed to elucidate their biological functions and pathways. Molecular docking was subsequently conducted to validate the binding affinity between nicotine and the core targets.

Results

Nicotine exhibited significant skin sensitization, neurotoxicity, and respiratory toxicity. A total of 160 common targets of nicotine and chronic wounds were identified, with TNF, IL6, and IL1B recognized as core targets. Enrichment analysis revealed significant involvement in inflammatory responses, the PI3K-AKT signaling pathway, the AGE-RAGE signaling pathway, and others. Molecular docking demonstrated strong binding affinity between nicotine and TNF (−5.6 kcal/mol) as well as IL6 (−5.0 kcal/mol).

Conclusion

Nicotine disrupts the homeostasis of the wound microenvironment by regulating core inflammatory factors such as TNF and IL6, inhibiting the PI3K-AKT repair pathway, and activating the AGE-RAGE metabolic toxicity pathway, thereby impeding the healing of chronic wounds. This study provides a multi-target network perspective on the toxic mechanisms of nicotine in wound healing and offers a theoretical foundation for clinical smoking cessation to promote wound recovery.