Multi-target therapeutic potential of Berberis vulgaris in systems biology through harmonious healing

Berberis vulgaris, a medicinal plant rich in the isoquinoline alkaloid berberine, has emerged as a promising multi-target therapeutic agent with broad-spectrum pharmacological activities. This review integrates evidence from systems biology, network pharmacology, and experimental studies to elucidate the complex mechanisms underlying its therapeutic efficacy. Berberine operates as a network modulator, interacting with multiple molecular targets organized within protein–protein interaction (PPI) networks and influencing key signaling pathways such as AMPK, NF-κB, PI3K–Akt, and MAPK. These interactions enable coordinated regulation of inflammation, metabolism, apoptosis, and cellular stress responses. A significant dimension of its activity involves modulation of the gut microbiota, where berberine reshapes microbial composition, enhances short-chain fatty acid production, regulates bile acid metabolism, and restores intestinal barrier integrity, collectively contributing to improvements in metabolic disorders including type 2 diabetes, obesity, and non-alcoholic fatty liver disease.
Additionally, berberine demonstrates potent synergistic effects with conventional antibiotics against multidrug-resistant (MDR) pathogens by inhibiting efflux pumps, disrupting biofilms, increasing membrane permeability, and re-sensitizing resistant strains. These properties position it as a valuable antibiotic adjuvant in addressing antimicrobial resistance. Besides, berberine exhibits significant neuroprotective effects in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Its mechanisms include inhibition of amyloid-beta production, reduction of tau hyperphosphorylation, attenuation of oxidative stress and neuroinflammation, preservation of mitochondrial function, and modulation of neurotransmitter systems and the gut–brain axis.This integrative mode of action highlights its potential as a foundation for novel therapeutic strategies in metabolic diseases, infectious diseases, and neurodegenerative disorders.