Hormesis as a universal cellular strategy for growth.

Abstract

Our review synthesizes a vast and dispersed literature to demonstrate that subtoxic doses of structurally diverse chemicals can induce a conserved growth-stimulatory (hormetic) response across bacterial, microalgal, plant, and mammalian cells. Stimulation is concentration- and exposure-time-dependent, with higher concentrations inhibiting growth. In eukaryotic models, moderate ROS signaling and activation of DNA-PKcs/Akt, ERK1/2, PI3K/AKT, mTOR, or AURKA accompany growth stimulation, with Cyclin D-CDK4 promoting G1/S transition in mammalian cells. The proliferative DNA-PKcs/Akt response is observed in human hepatic cells, while bacterial examples involve LuxR-dependent signaling and fatty acid β-oxidation. Metabolism rewires, with some microalgae enhancing glycolysis and Krebs cycling, whereas other photosynthetic microorganisms reroute photosynthetic carbon toward lipid or starch storage while downregulating selected carbohydrate-catabolic proteins. Nrf2-driven antioxidants in mammalian cells, carotenoids, and detoxifying enzymes are upregulated, establishing a preconditioned state that can attenuate apoptosis upon subsequent challenge. Within the Catabolic-Anabolic Cycling Hormesis (CACH) model, some time-dependent responses are consistent with an anabolic overshoot following a transient catabolic decline (ATP depletion). This anabolic reprogramming accompanies biofilm formation, altered motility, and, in neoplastic cells, anchorage-independent growth. Thus, cell proliferation is a metabolic strategy shaped by adversity, with functional consequences that depend on cellular context and the endpoint assessed.

Key Findings

• Subtoxic doses of diverse chemicals induce a conserved hormetic growth-stimulatory response across multiple cell types including mammalian cells.
• Nrf2-driven antioxidants and detoxifying enzymes are upregulated in mammalian cells, establishing a preconditioned state that can reduce apoptosis upon subsequent stress.
• Growth stimulation involves moderate ROS signaling and activation of pathways such as DNA-PKcs/Akt, ERK1/2, PI3K/AKT, and mTOR, accompanied by metabolic rewiring and anabolic reprogramming.

Clinical Significance

Citation

Agathokleous Evgenios, Markouizou Athina, Calabrese Edward Jet al.. Hormesis as a universal cellular strategy for growth. Archives of toxicology. 2026-Oct-23.