The hormetic landscape: from evolutionary origination to mechanistic pathways in therapeutics.

Abstract

Hormesis is a biphasic dose-response, where mild stress triggers adaptive defense responses that increase cellular resilience. The hormesis is now recognized as a core concept with applications in toxicology, metabolism, aging, and evolutionary biology. A historical review, evolutionary explanations, and recent molecular insights led to the concept of hormesis as an anticipatory, "predict-and-prepare" strategy that allows organisms to adapt to changing conditions are addressed. The mitohormesis, autophagy, xenohormesis, epigenetic remodeling, and their interdependence with signaling pathways (Nrf2-KEAP1, AMPK-SIRT1, NF-κB, and heat-shock response). The stress-induced reversal of differentiation in basal metazoans also defy the irreversible aging concept demonstrate conservative plasticity programs. The relevance of translational research using toxin-derived therapeutics and lifestyle-based hormetic interventions are discussed, including challenges of the hormetic zone, inter-individual variability, and bioactivity cliffs. The future scope of integrating AI and ML into nonlinear modeling of precise hormetic dosing, with considerable applications in aging, regenerative medicine, and precision therapeutics.

Key Findings

• Hormesis involves a biphasic dose-response where mild stress enhances cellular resilience through adaptive defense mechanisms.
• Nrf2-KEAP1 signaling pathway plays a critical role in mediating hormetic responses alongside other pathways like AMPK-SIRT1 and NF-κB.
• Hormetic interventions, including toxin-derived therapeutics and lifestyle modifications, have potential applications in aging, regenerative medicine, and precision therapeutics.

Clinical Significance

Citation

Verma Harshita, Kumar Gupta Ajay, Hema Get al.. The hormetic landscape: from evolutionary origination to mechanistic pathways in therapeutics. Cell cycle (Georgetown, Tex.). 2026-Dec.