First introduced by Southam and Ehrlich in 1943, hormesis is a phenomenon in which low doses of toxic substances or factors can positively affect cells or organisms by transiently disrupting cell homeostasis to induce adaptive responses, reduce background damage, and improve various health effects.^1,2 Specifically, hormesis not only decreases the rate of damage but also enhances cellular capacities to survive against subsequent stressors.³ Heat shock, radiation, chemical compounds (nanomaterials, heavy metals), physical activities, nutrient deprivation, and plant-derived compounds are among the known stimulants of a hormesis response.^4,5 Numerous studies have been conducted on the basic mechanisms of hormesis and different biological pathways, including the AMP kinase (AMPK) signaling pathway,⁶ the over-expression of heat shock proteins (HSPs),⁷ the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway,⁸ and hypoxia-induced response and mTOR.⁹

The beneficial health effects of hormetic stress have been reported for various health disorders. Physiological concentrations of homocysteine can induce biphasic effects on neurons and decrease the occurrence of Alzheimer’s disease by reducing the beta-amyloid aggregation process.¹⁰ The neuroprotective effects of the hormetic response were also established by other stimulants such as allicin, allopregnanolone, and raloxifene.¹¹ Furthermore, the potential hormetic effects of molecular hydrogen (H2) show benefit in the prevention and treatment of cardiovascular disease.¹² The wound healing effects of hormetic stress have been extensively studied.¹³ Keratinocytes, melanocytes, and fibroblasts, the major cellular components of the skin, are highly responsive to stress and are central to the aging process. As such, they offer an ideal model for studying hormetic stimulation with potential anti-aging and regenerative effects.

Importantly, most of the evidence discussed in this review is derived from in vitro skin cell systems and animal models, where exposure intensity, timing, and delivery conditions can be tightly controlled. Translation to human dermatology and cosmetic practice remains constrained by differences in barrier properties and microenvironment, formulation-dependent bioavailability, and limited clinical data on optimal hormetic dose windows and long-term safety. Accordingly, we present the following sections as mechanistic evidence and explicitly distinguish biological plausibility from clinical readiness.

Although hormesis has been explored in various systemic diseases and general aging, this review offers a focused and updated synthesis of the mechanisms and effects of hormetic stimulation specifically in skin cells. Unlike previous reviews, this article integrates findings on emerging hormetic agents such as nanomaterials, alongside more established inducers like heat stress and curcumin. We also examine the molecular mediators including, HSPs, Nrf2, and HO-1, that underpin these responses. This targeted analysis provides new insights into the potential applications of hormesis in dermatology and cosmetic science.

As the largest organ of the body, the skin comes directly in contact with various stressors, including UV radiation and environmental heat stress.¹⁴ Although these factors can increase the rate of skin disease, repeated heat stress can induce a hormetic response in skin cells and decrease their vulnerability to DNA damage (Figure 1).¹⁵ Heat stress was first introduced in drosophila and has since been extensively studied across species, including humans, and is responsible for a phenomenon called thermotolerance by the upregulation of the related genes and proteins.¹⁶ A mild heat stress (MHS) regimen (41°C for 1 hour/twice a week) has been widely used for in vitro studies and is well accepted for investigation of the hormetic response in human skin cells.¹⁷ Depending on the cell type, various effects were attributed to hormetic stress, including improved life expectancy, proteasomal activity, levels of various chaperone proteins, wound healing, angiogenesis, and differentiation.¹⁸

Figure 1.

Expression of heat shock proteins (HSPs), molecular chaperones that aid in cellular adaptation, DNA repair, development, and immune response, has been shown to increase in response to environmental heat stress and implicated in upregulating both pro- and anti-inflammatory pathways within tissues and organisms.^19,20 Within skin, a lack of HSPs can adversely affect overall skin health due to their role in skin integrity, keratinocyte differentiation, collagen synthesis, and inflammation (Figure 1).^21–23 In animal and human keratinocyte studies, hormetic stress induced by exposure to single and continuous MHS (at 38–42°C) can increase cell survival against other stimulants through overexpression of HSPs and other mechanisms.^24–26 For example, when exposed to heat stress following ultraviolet (UV) radiation, protective actions within the skin keratinocytes such as activation of phosphorylated Sirtuin 1 (SIRT1) and downregulation of tumor protein P53 gene (p53),²⁷ and activation of SP71 and HSP72,²⁸ may serve as therapeutic actions to reduce pathogenic responses within these cells. Skin fibroblasts were also shown to benefit from repeated heat exposure in both in vitro and in vivo studies. An in vitro analysis of repeated exposure on fibroblast enlargement found that in heat-stressed fibroblasts, the rate of cell enlargement was 2–3 times lower than in the control condition.²⁹ Similarly, in vivo work in humans showed that introducing mild and continuous heat stress can decrease the level of the autophagy marker protein, Microtubule-associated 1A/1B-light chain 3 (LC-3), and simultaneously increase its longevity-promoting effects.³⁰ Lastly, MHS has also been shown to induce melanogenesis within melanocytes,³¹ as well as exhibiting anti-aging effects through modulation of cellular morphology, cell proliferation, cytoskeleton integrity, and proteasome activity; as well as reduction of protein oxidation and increased cellular antioxidant capacity (Table 1).^17,29 One study showed that HSP90 attenuates exercise-induced cutaneous vasodilation via nitric oxide synthase (NOS), but only when core temperature is elevated ~1.0°C.³² Direct antioxidative effect of HSP90 obtained from duck muscle was shown in an in vitro study.³³ Surface plasmon resonance (SPR) showed that HSP90 could bind with both phospholipids and oxidized phospholipids, and prevent their further oxidation by the thiobarbituric acid reactive substances (TBARS) assay.³³ Several beneficial antiaging effects of MHS are listed in Table 1.

346595 Table 1.

It is important to distinguish in vitro heat exposure protocols from physiologic or clinical heat stress (sauna, localized thermal devices). In intact human skin, heat transfer is shaped by perfusion, sweating, epidermal barrier status, and spatial gradients across the epidermis and dermis, making direct extrapolation from uniform cell-culture heating to clinical dose windows uncertain. Therefore, reported in vitro mild heat stress parameters should be interpreted as mechanistic probes rather than prescriptive clinical regimens.

Curcumin, an active compound in turmeric, has anti-inflammatory properties that act to scavenge free radicals, replenish intracellular antioxidants, and activate antioxidant enzymes.⁴¹ Curcumin also has a unique role in triggering the hormetic stress response.⁴² Acting as a pro-oxidant agent, curcumin simulates the body’s antioxidant defense systems via the overexpression of Nrf2 and heme oxygenase-1 (HO-1) (Figure 2).^43,44 This occurs at low concentrations (below 20 μM), where in-vitro work in skin fibroblasts shows that curcumin activates the redox signaling pathway resulting in a large induction of HO-1; a process by which the body’s antioxidant defenses protect against the cell’s normal aging process.⁴⁵

Figure 2.

Curcumin demonstrated inhibitory effects on the proliferation of human skin fibroblasts at concentrations up to 10 μM. It was able to activate HO-1 but had no effects on the expression of HSP27, HSP90, and HSP70, even in the presence of heat shock. This confirmed the hormetic effects of curcumin by inducing mild oxidative stress, which in turn encouraged cells to overexpress HO-1 and Nrf2, the known actors in the curcumin-related hormetic response. Interestingly, in studies on human keratinocytes and fibroblasts, it appears that curcumin may also act to co-induce expression of HSPs (specifically HSP27, HSP90, and HSP70) in the absence of heat stress, which may be complementary to the heat stress hormetic adaptations discussed above.^46–48 Figure 2 is a summary of the hormetic effects of curcumin.

A recent study documented that curcumin was able to compensate for UV-irradiated damage in keratinocytes by manipulating the Nrf2 and HO-1 pathways and retrieving antioxidant capacities. Curcumin inhibited the SPAG5/FOXM1 pathway, which was responsible for inflammatory (Interleukin-1 beta (IL-1β), IL-6, IL-18) and apoptotic (Caspase 3, 8, Bax) responses in the irradiated cells.⁴⁹

One study on human epidermal keratinocytes showed that curcumin “at low doses (up to 1 μM for 24 h)” meaningfully increased chymotrypsin-like activity by 46% compared to that in untreated keratinocytes, which is a feature of hormesis.⁵⁰ Surprisingly, the effect of curcumin on 26S proteasome appears to be dose-dependent, where high doses of curcumin (≤10 µM) deactivated the 26S proteasomal degradation of IκBα, an inhibitor of nuclear factor kappa B (NF-κB), in cancer cells, and low doses (≥1 µM) increase proteasome activity.⁵¹ Furthermore, the expression of HSP 70 and 90 increased significantly after preincubation of human keratinocytes at 43°C for 1 hour followed by 24-hour treatment with 3 μM curcumin.⁵⁰ Similar effects were documented using kidney cells, where low curcumin concentrations (<10 μM) enhanced proteasome activity and HSP 30 and 70 accumulations, offering a hormesis response.⁵²

Nanomaterials (NMs) with a size of 1–100 nm are very enticing to the cosmetic industry due to their unique physicochemical properties that include offering added stability and potentially improved delivery performance and, in some formulations, enhanced skin deposition.^53,54 Gold and silver nanoparticles (NPs) are widely used in skin creams due to their antiaging, antibacterial, and antifungal properties.^55,56 The hormetic response induced by NPs was reported in human hepatoma cells where low concentrations of silver nanoparticles (Ag-NPs) induce cell proliferation and overexpression of p38 mitogen-activated protein kinase (p38 MAPK), which is a pivotal player in the hormesis response.⁵⁷ It has been shown that nanodiamonds (NDs) and silica nanoparticles (SiO2-NP) at low concentration (up to 0.5 μg/ml) can significantly increase cell viability, Nrf2 activity, SIRT1 and HO-1 expression and proliferation rates, and wound-healing capacity in normal human skin fibroblasts in culture.⁵⁸

Despite promising hormetic effects at low doses, nanomaterials can induce oxidative stress, inflammatory signaling, and cytotoxicity when exposure exceeds the adaptive window or when particle properties favor cellular uptake.^55,59 Skin penetration is also context dependent, with variability by formulation and route (including follicular delivery), and it may differ between intact and compromised skin barriers.^55,59 In addition, long-term persistence or accumulation, and particle characteristics such as size, coating, and surface charge can substantially modify bioactivity and toxicity profiles, supporting a case-by-case safety assessment.^55,59 Finally, regulatory expectations for nanomaterials in cosmeceuticals remain heterogeneous across jurisdictions, reinforcing the need for standardized characterization, exposure assessment, and long-term safety data alongside efficacy claims.^55,59

For clarity and comparison, the reported hormetic dose windows, exposure parameters, and principal signaling pathways for heat stress, curcumin, and nanomaterials in skin models are summarized in Table 2.

346598 Table 2.

Hormesis is well documented for its beneficial effects on various aspects of wound healing and can be triggered via chemical (NMs), natural (curcumin), and mechanical stimulants (heat stress).⁶⁰ The most important factors for wound healing are those that positively influence the viability, proliferation, and migration of keratinocytes and fibroblasts.⁶¹

Heat stress overexpresses HSP proteins in keratinocytes and fibroblasts, including HSP90.⁶² In an in vivo study, HSPs (HSP27, HSP60, HSP70, and HSP90) positively affected wound healing by inducing keratinocyte differentiation in mouse skin during wound healing.⁶³ HSP70 in keratinocytes is very effective in managing local inflammation and proliferation acceleration in an in vivo study in rats at the interface of polymer-implants.⁶⁴ Topical administration of curcumin not only decreased inflammatory biomarkers (IL-1β, Matrix Metalloproteinase-9 (MMP-9)), but also improved wound contraction, tissue granulation, fibroblast proliferation, and collagen synthesis in streptozotocin-induced diabetic rats.⁶⁵ Numerous studies have demonstrated the positive effects of curcumin on HSP expression, not only in human skin cells but also in human intestinal Caco-2 cells,⁶⁶ and rats subjected to sepsis.⁶⁷ In another in vivo study, it was shown that delivery of HSP70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis in Bagg Albino/cJ (BALB/cJ ) mice.⁶⁸ It was also shown that HSP90 utilizes a unique transmembrane signaling mechanism to promote skin cell migration in vitro and wound healing in vivo in mice.³⁴

This review highlights the hormetic effects of mild stressors specifically heat stress, curcumin, and nanomaterials on skin cells such as keratinocytes and fibroblasts. Mild heat stress was shown to enhance proteasome activity, antioxidant capacity, collagen expression, and cell survival, while curcumin activated the Nrf2/HO-1 pathway and improved inflammation control and wound healing. Low-dose nanomaterials stimulated cell proliferation, SIRT1 expression, and antioxidant defenses in selected experimental models, with dose and particle characteristics influencing the balance between adaptive signaling and toxicity. These effects are largely mediated through key stress-responsive pathways, including HSPs, Nrf2, and MAPK signaling. Collectively, the findings support the potential of hormetic stimulation as a strategy for skin regeneration and anti-aging interventions, but current evidence is predominantly preclinical and should be interpreted within clear translational boundaries. Among the strategies discussed, controlled thermal conditioning and curcumin-based approaches are conceptually closest to human application, whereas nanomaterial-driven hormesis remains more exploratory given uncertainties regarding penetration depth, long-term exposure, and regulatory oversight. Future work should prioritize standardized reporting of hormetic dose windows (intensity, duration, frequency), clinically relevant endpoints, formulation and delivery parameters, and long-term safety in well-designed human studies to enable safe, evidence-based translation into dermatologic and cosmetic practice.

No financial support was received from any organization.