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Network pharmacology of natural alkaloids: Rewiring the vicious cycle of mitochondrial dysfunction

Li He1, Yumei Zhuo2, Linlin Yang3

  • 1Department of Respiratory and Critical Care Medicine, The First People's Hospital of Shuangliu District, Chengdu, Sichuan, China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology
|November 1, 2025
PubMed
Abstract

Insights

Natural alkaloids can disrupt the vicious cycle of mitochondrial dysfunction by targeting multiple pathways. Further research is needed to improve their bioavailability and clinical application for chronic diseases.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Mitochondrial dysfunction forms a self-reinforcing vicious cycle network (VCN) involving bioenergetic failure, oxidative stress, calcium dysregulation, and defective quality control, driving chronic diseases.
  • Conventional single-target therapies are often ineffective against this interconnected pathology.

Purpose of the Study:

  • To review network-level mechanisms of natural alkaloids in modulating the mitochondrial VCN.
  • To analyze their multi-target engagement, context-dependent effects, and challenges for clinical translation.

Main Methods:

  • Comprehensive literature review of Web of Science and PubMed databases (2011-2025).
  • Focused search terms: "alkaloids", "mitochondria", "mitochondrial function", and therapeutic effects.

Main Results:

  • Alkaloids accumulate in mitochondria, engaging multiple VCN nodes simultaneously.
  • Compounds like berberine and matrine modulate energy metabolism, redox balance, and quality control pathways (e.g., AMPK/SIRT1/PGC-1α, Nrf2, PINK1/Parkin).
  • Network modulation yields context-dependent effects (cytoprotective in degenerative diseases, cytotoxic in cancer) but faces PK/PD challenges like poor bioavailability.

Conclusions:

  • Alkaloids present potent multi-target strategies for mitochondrial dysfunction.
  • Enhancing bioavailability, advanced predictive toxicology, and clinical validation are crucial for therapeutic realization.
Keywords:
AlkaloidsMitochondrial dysfunctionNanodeliveryNatural productOxidative stressPharmacological therapy

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