Plant-derived molecules as multitarget modulators of NF-κB, PI3K/Akt, MAPK, and AMPK/mTOR signaling in chronic diseases.

Cell signaling pathways regulate essential cellular processes including inflammation, oxidative stress, proliferation, apoptosis, metabolism, and immune homeostasis. Dysregulation of interconnected pathways such as NF-κB, MAPK, PI3K/Akt, Nrf2/ARE, JAK/STAT, AMPK/mTOR, and Wnt/β-catenin contributes significantly to chronic diseases including cancer, diabetes, cardiovascular disorders, neurodegenerative diseases, and inflammatory conditions. Increasing evidence indicates that plant-derived phytochemicals act as multitarget modulators capable of restoring signaling balance through simultaneous regulation of multiple molecular networks. This review provides an updated and integrative overview of phytochemical-mediated modulation of major signaling pathways involved in chronic diseases, emphasizing mechanistic cross-talk and translational relevance. A comprehensive literature survey was conducted using PubMed, SciFinder, and Google Scholar to collect experimental and clinical evidence on phytochemical regulation of signaling pathways. Major phytochemicals including curcumin, resveratrol, quercetin, berberine, epigallocatechin gallate, apigenin, and ginsenosides suppress NF-κB, PI3K/Akt, MAPK, and JAK/STAT signaling while activating Nrf2-mediated antioxidant defense, AMPK signaling, autophagy, and apoptosis. These compounds also regulate metabolic inflammation, neuroinflammation, mitochondrial dysfunction, and cancer-associated signaling networks. Unlike previous reviews focused on isolated pathways or individual compounds, this review integrates signaling cross-talk and multitarget phytochemical actions across diverse chronic diseases. Despite promising therapeutic potential, clinical translation remains limited by poor bioavailability, pharmacokinetic variability, lack of standardization, and insufficient large-scale clinical validation.