Targeting NF-κB Signaling in Preterm Labor: Molecular Mechanisms and Therapeutic Perspectives

Preterm labor is a leading cause of neonatal morbidity and mortality, with inflammation playing a central role in its pathogenesis. This structured literature review summarizes the role of the nuclear factor kappa B (NF-κB) signaling pathway in term and preterm labor and critically evaluates current evidence on natural and synthetic NF-κB modulators as potential therapeutic approaches. The narrative overview covers publications through June 2026. Experimental, translational, and review studies were synthesized narratively. NF-κB integrates hormonal, mechanical, infectious, and sterile inflammatory signals in gestational tissues, promoting the expression of pro-inflammatory cytokines, cyclooxygenase-2, prostaglandins, chemokines, and contraction-associated proteins that drive uterine activation. While tightly regulated NF-κB activation is essential for physiological term labor, it's premature or excessive activation contributes to inflammation-associated preterm labor. Natural compounds and synthetic agents consistently attenuate excessive NF-κB signaling and downstream inflammatory responses in preclinical models, supporting their potential as candidate therapeutic strategies. However, clinical evidence remains limited. Future research should prioritize tissue-specific, context-dependent modulation of NF-κB and establish the safety, optimal therapeutic windows, and clinical efficacy of NF-κB-targeted interventions during pregnancy.