Mechanistic Insights into Flavonoids in Cosmetic Applications: Multifunctional Roles and Formulation Considerations

Introduction

The demand for natural and effective cosmetic ingredients has surged as consumers become increasingly eco-conscious and aware of the potential health risks associated with synthetic compounds.¹ The cosmetics industry, responding to this shift, is prioritizing eco-friendly, sustainable formulations to meet the growing preference for products free of synthetic additives.² This trend aligns with broader global efforts to reduce the environmental impact of industrial development by choosing products that support ecological balance.³

One important driver of this shift is the increasing prevalence of antibiotic resistance, a public health threat that has been exacerbated by the widespread use of antibiotics in food, healthcare, and animal production. Antibiotic-resistant infections currently account for approximately 700,000 deaths worldwide each year,⁴ with projections indicating this number could rise dramatically without alternative antimicrobial solutions. As a result, researchers are actively pursuing plant-derived compounds that exhibit antimicrobial activity, such as flavonoids, which are known for their efficacy, low toxicity, and suitability for various applications, including cosmetics.^5–7 Although several papers have discussed the biological activities of flavonoids, few have focused on their multifunctional applications in cosmetics from a mechanistic perspective. Furthermore, the integration of formulation challenges, such as bioavailability and ingredient interactions, remains underexplored.

Synthetic preservatives, have long been used in cosmetics to prevent microbial growth and extend shelf life.⁸ However, studies have raised concerns about parabens’ potential to disrupt hormonal balance, cause allergic reactions, and contribute to long-term environmental damage by contaminating water systems.⁹ As consumers become more informed about these risks, the demand for natural preservatives has grown, positioning flavonoids as an ideal alternative due to their antimicrobial, anti-inflammatory, and antioxidant properties.^10,11

Contamination of cosmetics by pathogens like Staphylococcus aureus and Pseudomonas aeruginosa can occur at any stage of production or use, potentially leading to adverse health effects such as dermatitis and eye infections.^12,13 Regulations in cosmetic manufacturing emphasize microbial purity, but challenges remain in ensuring contamination-free products.¹³ Flavonoids, with their inherent antimicrobial effects, provide a natural solution to enhance the safety and longevity of cosmetic formulations.¹⁴ However, their incorporation into cosmetic formulations remains constrained by challenges such as limited aqueous solubility, instability under oxidative or pH conditions, and variable skin permeability.

The growing use of plant-based antimicrobial agents, including essential oils and plant extracts, reflects an industry-wide shift toward safer, multifunctional ingredients in cosmetics.¹⁴ Essential oils from plants such as tea tree, rosemary, and thyme are recognized not only for their antimicrobial benefits but also for their therapeutic effects, including anti-inflammatory and soothing properties.¹⁵ Polyphenol-rich plant extracts, including those containing flavonoids, have demonstrated notable antimicrobial and antifungal activity, further supporting their use in cosmetics as both preservatives and active skincare ingredients.¹⁶

Recent advancements in natural preservatives, such as silver nanoparticles and bioactive compounds like methylglyoxal from manuka honey, offer promising potential as effective antimicrobial agents in cosmetics.¹⁷ These innovations highlight a broader trend toward natural solutions that fulfill consumer preferences for safety and environmental responsibility without compromising product efficacy.¹⁸

Flavonoids are increasingly studied for their therapeutic potential in skincare. However, existing research has yet to fully integrate their mechanistic pathways, formulation challenges, and the comparative activity of different subclasses. This review evaluates current evidence on the biological functions of flavonoids, including their contributions to pigmentation regulation, antioxidant defense, antimicrobial activity, and epidermal barrier support. It also addresses practical challenges such as limited bioavailability, formulation instability, and insufficient clinical data. These issues highlight important gaps in the literature and support continued research aimed at optimizing the cosmetic application of flavonoids through scientifically grounded and sustainable approaches.

Whitening Effect of Flavonoids

Human skin pigmentation is among the most variable and visually apparent traits, yet the genetic foundations and evolutionary pathways of this complex characteristic remain incompletely understood.¹⁹ Existing research strongly indicates that natural selection has played a significant role in shaping the variation of this trait both within and between populations. A clear geographic trend shows that skin pigmentation is closely linked with latitude and the intensity of ultraviolet radiation (UVR).²⁰ The prevailing evolutionary theory, known as the vitamin D/folate hypothesis, suggests that this variation is a balance between the need for photoprotection and the requirement for vitamin D3 synthesis.¹⁹

Skin and hair color are primarily determined by the amount and distribution of melanin, while carotenoids and (de)oxyhemoglobin from dermal capillaries play a smaller role in pigmentation.²¹ Melanin not only defines pigmentation but also serves as a natural barrier against UV radiation by absorbing harmful rays.²² However, overproduction of melanin, often due to sun exposure, hormonal changes, or skin damage, can lead to hyperpigmentation.²³ This makes melanin a key target in skin-whitening treatments aimed at evening out skin tone and reducing dark spots.²⁴ Current research results show that melanin protects the human epidermis from ultraviolet radiation damage, but abnormal synthesis of melanin can lead to freckles, melasma, melanoma and other skin diseases.²⁵

The cAMP signaling pathway regulates melanin synthesis by upregulating MITF gene expression,²⁶ which stimulates tyrosinase production in melanocytes.²⁷ MITF acts as the master regulator of pigmentation, controlling the expression of tyrosinase and other melanogenic enzymes. UV radiation triggers this pathway via oxidative stress and inflammatory signals, increasing melanin synthesis as a protective response.^28,29 This process can be triggered by various stimuli, such as UV radiation, inflammatory cytokines, and hormonal changes. In cosmetics, many skin-lightening compounds work by inhibiting the activity of the tyrosinase enzyme, which leads to reduced melanin production while exerting minimal harmful effects on melanocytes.²⁵ Structurally, flavonoids interact directly with tyrosinase through hydrogen bonding, altering its active conformation and obstructing substrate entry. Specific structural features, such as the C2=C3 double bond, enhance their inhibitory activity, while methoxylation and glycosylation can reduce it.³⁰ For example, flavonoid-rich extracts from Coptis rhizome (pazentin A)³¹ and chrysanthemum petals³² demonstrate significant tyrosinase inhibition and melanin reduction in vitro and in human trials. The magnitude of tyrosinase inhibition varies substantially across flavonoid subclasses and is strongly influenced by hydroxylation patterns, conjugation, and steric features.^30,33 Most supporting evidence is derived from enzyme assays or cell-based models, and direct translation to topical efficacy remains inconsistent because cutaneous penetration and local stability are not uniform across compounds.^33,34

Flavonoids, as potent antioxidants, combat this process through multiple mechanisms. They neutralize reactive oxygen species (ROS) generated by UV exposure, reducing oxidative stress and inhibiting the downstream activation of the cAMP-MITF pathway. This leads to decreased tyrosinase production and reduced melanin synthesis.³⁵ Quercetin, one of the most extensively studied flavonoids, has been shown to significantly inhibit tyrosinase activity, leading to a marked reduction in melanin content.³⁶ In an in vitro study using B16 mouse melanoma cells, quercetin isolated from rose hip inhibited melanogenesis by suppressing intracellular tyrosinase activity and protein expression, without cytotoxicity.³⁷ In contrast, animal study reported that quercetin stimulated melanogenesis in mouse hair follicle tissues, enhancing melanin production in a concentration-dependent manner. The protein expression of tyrosinase and TRP-2 increased significantly, but their mRNA levels remained unchanged. This suggests that quercetin promotes melanogenesis by increasing the synthesis of key melanogenic proteins.³⁸ Similarly, inn human melanoma and normal human epidermal melanocytes, quercetin increased melanin production in a time- and dose-dependent manner. Tyrosinase activity was dramatically enhanced, with a 61.8-fold increase, while protein expression rose slightly. The effects involved both transcriptional and translational mechanisms.³⁹ These findings highlight the complex and dose-dependent effects of quercetin on melanogenesis, which vary between different cell types and experimental conditions.

In HMVII human melanoma cell line, several flavonoids, including kaempferol, rhamnetin, fisetin, apigenin, luteolin, chrysin, and genistein, were shown to enhance tyrosinase activity. These flavonoids stimulate melanogenesis by increasing intracellular tyrosinase activity, thereby promoting melanin production.⁴⁰ However, there are contradicting data in the literature. For example, kaempferide, a derivative of kaempferol, was found to inhibit tyrosinase activity,⁴¹ suggesting that certain flavonoids or their derivatives may have differing effects on melanogenesis depending on their chemical structure or concentration.

Flavonoid-rich extracts from plants like Portulaca oleracea and Sanbaixia demonstrate tyrosinase inhibition while also suppressing melanoma cell proliferation, highlighting their potential as safe, natural alternatives to synthetic whitening agents, which are known to cause irritation in some users.⁴² Related non-flavonoid polyphenols, including phenolic acids and stilbenes, also act as tyrosinase inhibitors in commonly used screening assays, and some display comparable inhibitory potency under identical conditions.^43–45 Head to head comparisons across compound classes remain limited,^46,47 which restricts robust ranking of flavonoids against other polyphenol families for cosmetic selection.

Beyond melanin regulation, flavonoids stabilize cell membranes by reducing lipid peroxidation, promote skin repair, and maintain collagen integrity, as shown in (Figure 1). These combined antioxidant, anti-inflammatory, and pigmentation-regulating effects underscore flavonoids’ potential as safe and effective agents for protecting against UV damage, hyperpigmentation, and premature skin aging.^48,49 Their ability to address multiple skin concerns, including hyperpigmentation, inflammation, and oxidative damage, makes flavonoids invaluable as multifunctional ingredients in modern skincare formulations. These formulation factors should be considered alongside in vitro potency when identifying candidate flavonoids for depigmenting applications.

Table 1 Comparative Summary of Flavonoids and Their Key Cosmetic Applications, Mechanisms, and Evidence Levels

Figure 1 Mechanisms of Flavonoids in Regulating Skin Pigmentation and UV Protection. Flavonoids neutralize ROS and inhibit the cAMP-MITF pathway, reducing melanin synthesis. They also suppress NF-κB activation, reducing cytokine release and preventing collagen degradation, helping to maintain skin integrity. ↑ = increase; ↓= reduce; + = activation; ⊥= Inhibition. Created with Biorender.com.

Antioxidant Effect of Flavonoids

Oxidative stress, along with the damage it causes, can intensify pigmentation and accelerate skin aging, resulting in uneven tone, wrinkles, sagging, dryness, and a rough texture.^62–64 Flavonoids, as potent antioxidants, help reduce oxidative damage by scavenging free radicals and enhancing the activity of antioxidant enzymes (Table 1).⁶⁵ In particular, their radical-scavenging ability is linked to their structure, where multiple hydroxyl groups donate electrons to neutralize ROS efficiently.⁶⁵ These hydroxyl-rich structures also allow flavonoids to interact directly with reactive oxygen species, neutralizing harmful compounds like peroxyl radicals and superoxide anions.⁶⁶ Several studies support that specific hydroxylation patterns in flavonoids contribute to higher radical-neutralizing efficiency, with notable effects against ROS generated by UV exposure and pollution.¹⁰ The antioxidant properties of flavonoids help protect against damage from free radicals by neutralizing ROS, activating antioxidant enzymes, inhibiting oxidases like xanthine oxidase (XO), cyclooxygenase (COX), lipoxygenase, and phosphoinositide 3-kinase (PI3K), and reducing α-tocopheryl radicals.⁶⁷ Moreover, research indicates that flavonoids can stabilize cell membranes by reducing lipid peroxidation, a crucial factor in maintaining skin integrity and preventing signs of premature aging.⁶⁸ This stabilization effect is achieved by decreasing malondialdehyde levels,⁶⁹ a byproduct of lipid peroxidation commonly associated with oxidative skin damage.^64,70 Flavonoids also contribute to raising uric acid levels, enhancing metal-chelating capacity, and boosting low-molecular-weight antioxidant activity, thereby mitigating oxidative stress.⁶⁷ Antioxidant rankings are highly assay-dependent, and radical scavenging assays do not necessarily predict efficacy in the stratum corneum or viable epidermis.⁷¹ Differences in skin permeability, partitioning into lipid domains, and formulation microenvironment can substantially alter apparent antioxidant performance after topical application.⁷²

Free radicals, such as ROS, are produced through normal metabolic processes but are increased by external factors like UV radiation, pollutants, and toxins.⁷³ Excessive ROS can lead to lipid peroxidation, protein damage, and DNA mutations, which accelerate skin aging and increase the risk of diseases such as cancer.^74,75 By protecting cell structures from oxidative stress, flavonoids support cellular resilience and integrity.⁷⁶ Flavonoids, due to their polyphenolic structure, are effective at neutralizing these harmful radicals and stabilizing cell membranes (Figure 1).⁷⁷

Several flavonoids are used in cosmetic formulations as effective antioxidants to protect the skin against oxidative stress and photo-induced ageing. Quercetin, rutin, hesperidin, and apigenin are among the most extensively investigated flavonoids due to their ability to scavenge reactive oxygen species, inhibit lipid peroxidation, and reduce UV-induced skin damage.⁷⁸ Apigenin, a plant-derived flavonoid, exhibits strong antioxidant properties beneficial for cosmetic applications. It effectively scavenges reactive oxygen species (ROS), reduces oxidative stress, and protects skin cells from UV-induced damage. In an in vitro study using human dermal fibroblasts derived from a healthy 31-year-old male, rutin demonstrated significant photoprotective effects against UVA-induced damage. Rutin enhanced cell viability and reduced photo-oxidative stress by lowering intracellular ROS levels. These effects were mediated through activation of the Nrf2 transcriptional pathway, which led to increased reduced glutathione levels, an elevated Bcl-2/Bax ratio, and preservation of mitochondrial respiratory function (Table 1).⁷⁹ The findings suggest that rutin exerts cytoprotective and anti-apoptotic effects in UVA-exposed skin cells.

An emerging area of research emphasizes the synergy between flavonoids and other natural antioxidants, such as vitamin C and E, where they can collectively enhance antioxidative effects more effectively than when used in isolation.⁸⁰ The reported synergy is context-specific and depends on concentration ratios, pH, and the presence of transition metals or peroxides in the formulation.^81,82 In addition, certain polyphenols can exhibit pro-oxidant behavior under specific experimental conditions, which supports the need for stability testing within the final vehicle rather than reliance on chemical assays alone.⁸³

Studies have shown that human diseases, cancer, and skin aging and sensitivity are strongly related to oxidative stress.^64,84 At present, the antioxidant evaluation methods of cosmetics are mainly summarized as scavenging free radical ability, enhancing antioxidant oxidase activity and reducing ROS levels.^67,68 In vitro antioxidant methods mainly include free radical scavenging ability tests, including scavenging oxygen free radicals (ORAC method), scavenging DPPH free radicals (DPPH method), total antioxidant capacity test (ABTS method).^85–87 Cellular methods mainly induce cells to produce ROS models through ultraviolet and ozone, and test cell morphology and survival rate.⁸⁸ In addition, ROS and antioxidant enzyme activities were detected to evaluate the antioxidant effect of cancer.⁸⁹ At the same time, it can also be evaluated by the relevant indicators of animal post-molding detection. Studies have shown that total polyphenols have good antioxidant activity due to the presence of several phenolic hydroxyl groups.⁹⁰ Ji et al⁹¹ used ascorbate (Vc) as a positive control to test the scavenging ·OH and ABTS free radicals and the reducing ability of Fe3+ (FRAP) of brown pigment extracted from hazelnut shell.⁹¹ Notably, several studies report that flavonoid-rich extracts achieve radical scavenging activity comparable to standard antioxidants such as vitamin C at matched concentrations, although outcomes vary with extraction method, assay type, and endpoint selection.^92–94 Vitamins C and vitamin E are widely used for their capacity to neutralize free radicals, reduce UV-induced erythema, and support collagen synthesis.⁹⁵

Anti-Inflammatory Effects of Flavonoids

Inflammation is a protective physiological response to external stimuli, including allergens, pollutants, and pathogens, but excessive inflammation, such as in acne and allergic reactions, leads to tissue damage in the skin.^96,97 Macrophages play a central role in inflammation regulation: M1 macrophages secrete pro-inflammatory factors, initiating inflammation,⁹⁸ while M2 macrophages release anti-inflammatory factors that support tissue repair.⁹⁹

A common method for evaluating anti-inflammatory efficacy in vitro is the LPS-induced RAW264.7 macrophage model, which measures the reduction of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6.^100,101 With increasing consumer demand, the cosmetics industry is incorporating natural anti-inflammatory compounds, such as flavonoids, into formulations aimed at reducing acne and calming irritated skin. Plant-derived flavonoids have gained attention in recent years for their safety, non-toxicity, and effectiveness in reducing inflammation.¹⁰² Flavonoids exert these effects primarily by inhibiting the NF-κB pathway, a central regulator of inflammatory gene expression. By reducing oxidative stress and pro-inflammatory cytokine release, flavonoids promote a shift toward tissue repair and barrier recovery. For example, flavonoid glycosides from Tilia leaves, including kaempferol-3,7-O-dirhamnoside and quercetin-3,7-O-dirhamnoside, showed significant anti-inflammatory effects in a benzoquinone-induced swelling model.^102,103 Flavonoids also regulate tight junction proteins such as claudins and occludins through activation of the aryl hydrocarbon receptor (AhR) in keratinocytes, strengthening the physical barrier against irritants and preventing water loss.¹⁰⁴

Beyond cytokine inhibition, flavonoids (eg. Quercetin 3-O-β-D-Glucuronide) influence lipid metabolism, natural moisturizing factor (NMF) production, and tight junction regulation, key processes in restoring skin hydration and integrity.¹⁰⁵ Quercetin is a key natural antioxidant widely applied in cosmetics, nutraceuticals, and pharmaceuticals for its anti-inflammatory and protective properties.¹⁰⁶ Despite its benefits, its low hydrophilicity and limited skin absorption hinder its use in topical formulations.

For instance, studies have shown flavonoids not only reduce inflammation but also promote tissue repair by stimulating lipid synthesis (ceramides and fatty acids) and improving transepidermal water loss (TEWL) (Figure 2).^107,108 Apigenin has demonstrated notable anti-inflammatory activity, making it a valuable compound in cosmetic formulations. It downregulates proinflammatory mediators such as COX-2 and iNOS, and inhibits NF-κB signaling pathways, thereby reducing skin inflammation.¹⁰⁹ These dual effects significantly enhance the skin’s capacity to retain moisture, restore its protective barrier, and defend against environmental irritants (Table 1). By simultaneously reducing inflammation and promoting key processes such as barrier repair and hydration, flavonoids emerge as powerful multifunctional agents that support skin resilience, elasticity, and overall health.

Figure 2 Anti-inflammatory and Barrier Repair Mechanisms oft Flavonoids. Flavonoids inhibit NF-κB and cytokine release, promoting lipid synthesis and restoring the skin barrier. They enhance NMF production and regulate tight junction proteins, improving hydration and reducing irritation. ↑ = increase; ↓ = reduce. Created with Biorender.com.

Anti-Allergy Effects of Flavonoids

Flavonoids are recognized for their potential in managing skin sensitivity and reducing allergic reactions, making them valuable ingredients in sensitive skincare formulations. Allergic reactions in sensitive skin are often driven by mast cell activation and mediator release, which represents a mechanistic layer distinct from cytokine-dominant inflammatory models.¹¹⁰ When activated via allergens and IgE, mast cells release histamine, proteases, and chemotactic agents, triggering acute inflammation and driving chronic allergic responses through cytokine production. Overactivation heightens cytokine and chemokine levels, intensifying inflammation and disease.¹¹¹

Skin sensitivity is not classified as a disease but rather as a heightened response to environmental factors, leading to symptoms like dryness, tightness, redness, itching, and tingling.^112–114 These symptoms are often due to structural differences in the skin and increased responsiveness of sensory nerves.

Several factors contribute to skin sensitivity: (1) Impaired skin barrier function, often due to a thinner stratum corneum, which makes the skin more susceptible to irritants. (2) Neurological factors, as increased sensitivity in skin nerves, is linked to abnormal central and peripheral nerve function. (3) Heightened inflammatory responses, as a weakened barrier makes sensitive skin more vulnerable to inflammation from external allergens.^115,116 Flavonoids strengthen the skin’s barrier function and reduce nerve sensitivity, providing comprehensive support for managing sensitive skin (Figure 3).^116,117

Figure 3 Flavonoid Mechanisms in Reducing Skin Sensitivity and Allergic Inflammation. Flavonoids strengthen the skin barrier, reducing permeability and attenuating sensory nerve activation. By inhibiting the release of pro-inflammatory mediators like histamine and β-hexosaminidase, flavonoids suppress allergic reactions and downstream inflammatory pathways, mitigating skin irritation and enhancing dermal resilience. ↓ = reduce. Created with Biorender.com.

Flavonoids are popular in cosmetics for their anti-allergic properties.¹¹⁸ Flavonoids like dihydromyricetin (DHM) help mitigate mast cell-mediated allergic inflammation by inhibiting NF-κB activation, reducing cytokine release (TNF-α, IL-6), and suppressing STAT5 phosphorylation and tryptase production.¹¹¹ Studies show that flavonoids like quercetin and specific ginseng-derived flavones are effective anti-allergic agents,¹¹⁸ significantly inhibiting β-hexosaminidase release, a marker of allergic response, without causing cytotoxicity even at higher concentrations.¹¹⁹ This activity highlights quercetin’s suitability for products targeting sensitive and allergy-prone skin.

Commonly used evaluation methods include barrier function repair assays, inflammation suppression tests, and nerve desensitization models.¹²⁰ Specifically, assays like histamine release and β-hexosaminidase inhibition are often used to measure the effectiveness of flavonoids in reducing allergic responses.¹²¹ Histamine, a compound often released during allergic reactions, is inhibited by flavonoids, thus reducing symptoms of redness, itching, and swelling in the skin.¹²² Flavonoids also suppress key pro-inflammatory mediators, including IL-4, IL-13, and CD40 ligand, primarily by downregulating the NFAT and AP-1 signaling pathways.¹²³ These mechanisms contribute to their broader anti-allergic activity, positioning flavonoids as promising dietary agents for allergy prevention and symptom relief.

Antibacterial Effect

Microbial contamination in cosmetics can degrade active ingredients, producing byproducts that cause skin irritation, allergies, or infections.¹²⁴ To minimize these risks, preservatives are used; however, synthetic preservatives in excess can lead to skin sensitivity and other safety concerns.^3,125 Flavonoids, known for their natural antimicrobial properties, offer a safer alternative, enabling potential preservative-free formulations that still inhibit microbial growth—an advantage for cosmetics designed for sensitive skin.^3,126,127

According to established cosmetic safety standards, microbial testing in cosmetics typically screens for pathogens like Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger.^128,129 Evidence suggests that flavonoids can inhibit these microbes, possibly reducing the need for synthetic preservatives.^126,127,130

Acne Prevention and Treatment

Acne is a chronic inflammatory condition affecting hair follicles and sebaceous glands, often exacerbated in adolescents due to increased androgen levels.¹³¹ Elevated androgens stimulate excess sebum production and accelerate keratinocyte proliferation, leading to blocked pores and trapped sebum, creating an ideal environment for Propionibacterium acnes and resulting in inflammation and acne lesions.¹³² Flavonoids, with their anti-inflammatory and sebum-regulating properties, are under study for their potential in acne prevention and treatment. For example, a study demonstrated that licorice flavonoids can effectively treat acne by modulating skin microbes, thereby disrupting acne development and promoting a microecological balance similar to that of healthy skin in rats. Licorice flavonoids achieved this by reducing pro-inflammatory bacteria populations and supporting beneficial microbial growth, providing an integrative approach to acne management.¹⁸ Furthermore, the study clarified the anti-acne action of LCF, which works by balancing metabolism and microbial communities. This discovery provides a theoretical foundation that could guide future formulation development and clinical use of this treatment.¹⁸

Flavonoids like genistein and daidzein exhibit mild estrogen-like properties, mimicking estrogen in reducing sebum production by inhibiting enzymes like histidine decarboxylase and catechol-O-methyltransferase.¹³³ This activity helps counteract androgen-induced sebum overproduction, a key contributor to acne.¹³⁴ These properties make flavonoids ideal for acne-prone formulations. The gentle, non-irritating action of these flavonoids also makes them suitable for sensitive and inflamed skin types.

Flavonoids reduce inflammation by downregulating pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. For instance, kaempferol and quercetin are shown to inhibit the NF-κB pathway,¹³⁵ reducing inflammation and swelling associated with acne lesions (Figure 4). This anti-inflammatory effect supports skin recovery and decreases the severity of acne symptoms.¹³⁶

Figure 4 Mechanisms of Flavonoids in Acne Prevention and Skin Health Improvement. Flavonoids exert multiple actions to prevent acne and improve skin health. Luteolin and apigenin generate reactive oxygen species (ROS), inhibiting P. acnes and reducing inflammation. Genistein and daidzein reduce sebum production by inhibiting sebogenic enzymes, preventing pore blockage. Licorice flavonoids modulate the skin microbiome, lowering P. acnes levels and restoring microbial balance. Kaempferol and quercetin suppress inflammation by inhibiting the NF-κB pathway, reducing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and promoting skin healing. These combined mechanisms contribute to acne prevention and enhanced skin health. ↑ = increase; ↓ =reduce; ⊥= Inhibition. Created with Biorender.com.

Some flavonoids exhibit direct antimicrobial effects against acne-causing bacteria. Luteolin and apigenin, for example, have been shown to inhibit P. acnes by disrupting bacterial cell walls and generating ROS that lead to bacterial cell death.^137,138 This mechanism highlights flavonoids’ suitability as natural antibacterial agents in acne treatment. Human skin studies confirm that flavonoids like genistein are non-toxic and non-irritating, making them suitable for cosmetic applications targeting acne.⁴⁸ Several flavonoids have shown promising therapeutic effects in the treatment of acne vulgaris. Licorice flavonoids such as licochalcone A, licochalcone C, licoflavone A, neobavaisoflavone, liguiritigenin, and isoliquiritigenin are known to inhibit the PI3K-Akt signaling pathways, which are involved in cell proliferation and inflammation.⁴⁸ These flavonoids also reduce mitochondrial activity, contributing to their anti-acne effect. Additionally, quercetin, a well-known flavonoid, has been shown to suppress the production of proinflammatory cytokines in P. acnes-stimulated cell lines. Quercetin also reduces TLR-2 expression, MMP-9 mRNA levels, and MAPK phosphorylation, thereby inhibiting the inflammatory response.¹³⁹ Furthermore, quercetin demonstrates antibacterial activity against P. acnes, the bacteria responsible for acne lesions.¹⁴⁰ These flavonoids, through their combined anti-inflammatory, antibacterial, and signaling pathway-modulating effects, present significant potential for acne vulgaris treatment.

The combination of these properties—sebum regulation, anti-inflammatory action, and antibacterial effects—positions flavonoids as highly versatile agents in acne-prevention formulations that can address multiple acne-related factors naturally and effectively.

Moisture Function of Flavonoids

Moisturizers are crucial in daily skincare routines, particularly when the epidermal barrier is compromised or skin hydration is reduced, as they help restore and maintain skin’s moisture balance and integrity.¹⁴¹ The multiple hydroxyl groups present in flavonoid glycosides enable the formation of hydrogen bonds with water molecules, effectively trapping moisture within the skin and reducing transepidermal water loss. This mechanism enhances skin hydration and maintains its elasticity and smoothness.¹¹⁷ The ability of flavonoids to act as both humectants and emollients further supports their function in improving skin moisture by attracting and holding water while also smoothing the skin’s surface.

Maintaining optimal water content is crucial for a healthy skin barrier and provides various health and cosmetic benefits. Three key components that support skin hydration are natural moisturizing factors, the skin’s lipid bilayer, and hyaluronic acid. These elements help sustain moisture within the epidermis and deeper skin layers, promoting a robust skin barrier.¹⁴² Natural moisturizing factors (NMF) consist of powerful humectants that draw and retain water from the environment, essential for hydration in the stratum corneum. Filaggrin, a large protein in the corneocyte layer, is broken down into NMF in the upper layers of the stratum corneum.^143–145 This process, known as proteolysis, depends on water activity within corneocytes and external humidity levels, occurring only within a specific range of water activity.¹⁴⁶ Notably, UV radiation can disrupt the natural breakdown of filaggrin into NMF, reducing hydration.¹⁴⁷ Additionally, certain flavonoid aglycones, such as genistein, contribute to skin hydration through their phenolic hydroxyl groups, which improve water retention.¹⁴⁸

Flavonoids inhibit hyaluronidase, an enzyme responsible for the degradation of hyaluronic acid, preserving HA levels in the dermis.¹⁴⁹ Intact HA interacts with CD44 receptors on dermal fibroblasts, triggering signaling pathways that promote the production of additional hyaluronic acid and collagen.¹⁵⁰ These processes reinforce hydration, elasticity, and skin smoothness. Collagen fibers provide a scaffold within the extracellular matrix (ECM), supporting HA and glycosaminoglycans, which retain water and contribute to skin hydration (Figure 5).^151,152

Figure 5 Mechanisms of Flavonoids in Enhancing Skin Hydration and Structural Integrity. Flavonoids promote skin hydration and elasticity through two key pathways. By inhibiting hyaluronidase, they preserve hyaluronic acid (HA), which activates CD44 on fibroblasts to stimulate HA and collagen synthesis, reinforcing the extracellular matrix (ECM). Additionally, flavonoids neutralize ROS, suppress inflammation, and inhibit matrix metalloproteinases (MMPs), preventing collagen breakdown. These combined actions support skin hydration, elasticity, and barrier function. ↑ = increase; ↓ =reduce. Created with Biorender.com.

Flavonoids also help enhance moisture retention by reinforcing the skin’s barrier function and stimulating dermal fibroblasts to produce collagen and hyaluronic acid—key components for maintaining hydration, elasticity, and overall skin integrity.¹⁵³ Together, these combined properties make flavonoids an invaluable ingredient in skincare formulations, offering natural, effective support for maintaining skin hydration, elasticity, and overall health.

Delay Skin Aging Effect of Flavonoids

Skin aging is a multifactorial process primarily driven by factors such as oxidative stress, collagen breakdown, hormonal changes (eg., reduced estrogen), and prolonged UV exposure. These factors contribute to common signs of aging, including wrinkles, sagging, dryness, and a loss of elasticity. Flavonoids, with their potent antioxidant and anti-inflammatory properties, play a crucial role in combating these age-related changes.¹⁵⁴ By neutralizing free radicals, inhibiting collagen-degrading enzymes, and stimulating collagen production, flavonoids help preserve skin structure and prevent visible signs of aging.^117,155,156 A substantial proportion of anti-aging evidence is derived from in vitro fibroblast systems¹⁵⁷ and UV-induced animal models,¹⁵⁸ which provide important mechanistic insight and preliminary efficacy signals. However, broader validation in well-controlled human studies remains limited and often show constrained representativeness, with most trials enrolling predominantly female participants, relatively small to moderate sample sizes, and restricted age ranges. Many studies also recruit from narrow geographic populations, which limits generalizability and complicates mechanistic interpretation when participants are selected primarily on clinical features of aging.¹⁵⁴

The polyphenolic structure of flavonoids allows them to scavenge free radicals, preventing oxidative damage. Flavonoids neutralize superoxide anions, chelate metal ions to block hydroxyl radicals, and inhibit lipid peroxidation, protecting skin cells and maintaining structural integrity.^65,159,160 These antioxidant effects are particularly important in mitigating the damage caused by UV-induced oxidative stress, a primary contributor to skin photoaging.^161,162 Flavonoids stimulate fibroblasts to increase collagen and hyaluronic acid production, key for maintaining skin firmness and elasticity. The mild estrogen-like activity of flavonoids like genistein further supports collagen integrity, countering age-related decline.¹⁶³ By reducing inflammation and absorbing UV rays, flavonoids help protect against photoaging.¹⁶⁴ Their ability to inhibit enzymes involved in collagen degradation also aids in preserving skin structure.¹⁶⁵ In an animal study, Naringenin, a flavonoid from citrus fruits, demonstrated potential in preventing UV-induced photoaging. When incorporated into a microemulsion and loaded into Sericin gel, NAR reduced UVB-induced wrinkles, erythema, and other signs of photoaging.¹⁶⁶ This formulation protected the skin from UV-induced damage, suggesting its potential for use in anti-aging cosmetic products.

Studies indicate that topical formulations containing flavonoid extracts can improve clinical or instrumental signs associated with photoaging, although effective concentrations and durability of benefit appear to depend on extract composition, vehicle design, and treatment duration.^167,168 Flavonoids such as quercetin, luteolin, and genistein are widely used in anti-aging formulations for their proven efficacy in reducing oxidative stress, supporting collagen production, and protecting against UV-induced damage.¹⁶⁹ Fr example, hesperidin (HSD) shows potential in anti-aging cosmetics by inhibiting collagenase, offering antioxidant and UV-protective effects. HSD-loaded nanoemulsions enhance skin hydration, reduce wrinkles, and protect against UV damage,¹⁷⁰ making it a promising ingredient for skin care. Apigenin, a flavonoid with antioxidant properties, counteracts UVA-induced skin aging by restoring fibroblast viability and inhibiting MMP-1 expression, thereby preserving collagen integrity. In a clinical trial, apigenin-containing cream improved dermal density, elasticity, hydration, and reduced fine wrinkles, supporting its potential as an effective anti-aging agent.⁵⁵

Flavonoids’ broad range of biological activities is driven by several interrelated molecular mechanisms that regulate key skin functions such as pigmentation, elasticity, hydration, and protection from environmental stressors. These effects, discussed in detail throughout this paper, are mediated through the inhibition of key enzymes, modulation of inflammatory and oxidative pathways, and the enhancement of structural proteins in the skin. The following table provides a summary of these primary mechanisms, their regulatory pathways, and their corresponding cosmetic applications, highlighting the versatility of flavonoids in skincare formulations (Table 2).

Table 2 Molecular Mechanisms and Regulatory Pathways of Flavones in Skin Health

Flavonoids, including quercetin, rutin, and catechins, are widely utilized in cosmetic formulations due to their wide range properties. However, their application is limited by several factors. These compounds often exhibit poor solubility in lipophilic media, which can impair their effectiveness in skin care products.^187,188 Flavonoids face challenges with skin penetration, as their molecular structure hinders efficient absorption through the skin barrier.^34,189 Their stability can also be compromised under exposure to light, heat, and air, reducing their long-term efficacy in formulations.³⁴ Despite these limitations, ongoing research into enhancing their bioavailability and stability offers promising solutions for their improved use in cosmetics.

Safety and Toxicity Considerations

Under cosmetic use conditions, flavonoids are generally considered safe when appropriately formulated and used at cosmetic-relevant concentrations,⁴⁸ with safety evaluation focusing primarily on local skin tolerance and photo-safety rather than systemic toxicity. Commonly used cosmetic flavonoids include quercetin and rutin, apigenin, luteolin, and the isoflavone genistein.¹⁹⁰ Topical quercetin formulations are well tolerated in both in vitro skin models and in vivo animal dermatitis models when adequately solubilized, minimizing irritation risk.^191,192 Apigenin and luteolin show low irritation potential in in vitro and in vivo skin models, with anti-inflammatory and anti-photoaging activity,⁵² while genistein, despite documented topical safety in controlled human studies, requires particular attention due to its estrogenic activity, emphasizing the importance of limiting systemic absorption (Table 1).⁵⁹ A study assessed the safety of luteolin, apigenin, quercetin, and genistein using multiple in vitro, in vivo, and computational models. The authors tested developmental toxicity in the chicken embryo model, where luteolin and genistein exhibited significant developmental toxicity, with mortality rates reaching 43.75% and 50% at higher doses, respectively. Quercetin and apigenin demonstrated lower mortality, but still affected developmental indices and liver weight. The Ames mutagenicity test indicated that all compounds showed signs of mutagenicity, with quercetin and luteolin exhibiting the highest mutagenic indices (up to 1.4–1.9). In silico toxicity predictions using the T.E.S.T. model classified all compounds as developmental toxicants, with genistein and luteolin also flagged for mutagenicity risks.¹⁹³ Genistein has been associated with endocrine and hypersensitivity effects. A human study reported a 19% decrease in serum testosterone in healthy men after four weeks of high soy protein intake, although results across studies are inconsistent.¹⁹⁴ Additionally, genistein-containing soy products can cause allergic reactions, typically mild and often beginning in childhood, with symptoms such as eczema, pruritus, gastrointestinal discomfort, and skin erythema, while severe reactions are rare.¹⁹⁵ These results highlight the potential risks associated with the use of flavonoids, with varying degrees of toxicity observed across different models. Although several studies show favorable outcomes, careful formulation and dose control are essential to minimize risks, particularly regarding endocrine disruption and allergic reactions. Therefore, the use of flavonoids in cosmetics requires rigorous safety evaluation to prevent adverse effects.

Conclusion and Future Perspectives

Flavonoids have emerged as a highly promising group of ingredients in cosmetics, showcasing a wide range of bioactive properties that address various skin concerns. Their effectiveness in skin whitening, antioxidant defense, anti-inflammatory modulation, antimicrobial protection, and anti-aging is well documented, positioning them as versatile compounds in skincare and other cosmetic applications. By modulating key molecular pathways such as tyrosinase inhibition, ROS scavenging, NF-κB suppression, and collagen production, flavonoids offer multifunctional benefits that align with the increasing consumer demand for natural, sustainable cosmetic products. However, challenges related to poor bioavailability, skin penetration, and formulation stability remain, limiting their practical application. Ongoing research aimed at enhancing the stability and delivery of flavonoids, particularly through emerging technologies like nanocarriers and other advanced delivery systems, holds promise for overcoming these barriers and expanding their role in cosmetics.

The future of flavonoid-based cosmetic formulations lies in overcoming critical formulation challenges and leveraging emerging delivery technologies. There is a significant need for innovative delivery systems, such as nanocarriers, liposomes, and other targeted vehicles, which can improve flavonoid stability, solubility, and skin penetration, thereby enhancing their bioavailability and therapeutic potential. In addition, research into ingredient interactions should be prioritized to better understand how flavonoids work synergistically with other natural compounds, further amplifying their effectiveness. Currently, the majority of research on flavonoids focuses heavily on cell-based studies, but there is a pressing need for animal studies and clinical trials to validate their in vivo efficacy and long-term safety. These studies are crucial to translate laboratory findings into safe, effective cosmetic products for broader consumer use. Furthermore, addressing regulatory considerations and establishing standardized safety protocols will be pivotal to gaining consumer trust and ensuring the widespread adoption of flavonoid-rich formulations. As these research gaps are addressed, flavonoids have the potential to revolutionize the cosmetic industry, offering a safe, eco-friendly, and multifunctional alternative to synthetic ingredients.