profile iconIngredient Profile
Common Name
Hesperidin Methyl Chalcone
Hesperidin Methyl Chalcone
Citrus fruits
Present in
Vitamin X
Barrier Repair


klingman iconKligman Ingredient Evaluation
Poor Penetration
Biochemical Mechanism
  • Filaggrin and B-glucocerebrosidase inducer
  • NF-kB, IL inhibitor
  • Anti-MMP activity
Level of evidence
Level B, Good Quality Evidence

Regimen Lab Skincare Encyclopedia

Hesperidin Methyl Chalcone

V 1.0 last edited 06May2022


  • Usage rate at 0.05-2%
  • Antioxidant, Anti-dark Circle, Barrier Repair, Anti-inflammatory
  • Super duper yellow

Regimen's Take

Hesperidin Methyl Chalcone (HMC) is a very interesting antioxidant as it is one of the rare Barrier Repair Antioxidants. It is able to increase Filaggrin and B-glucocerebrosidase which are essential for Ceramide production. The other notable use for HMC is its ability to reduce capillary permeability for dark cicles around the eyes. One major drawback is its super bright color; it is highlighter yellow and can stain anything it touches. Using it at high concentrations can make your skin appear jaundiced.

What is Hesperidin Methyl Chalcone?

Hesperidin methyl chalcone (HMC) is a flavonoid that has strong free radical quenching properties and is a highly complex compound typically found in bright coloured plants and flowers. In skincare, it’s primarily used as an antioxidant, with noted effects on circulation for reducing dark circles and melanin synthesis. Hesperidin in its raw form has poor absorption, hence, it is modified into HMC to allow for better stability and skin compatibility. Hesperidin has been shown to reverse side effects such as thinning skin caused by the use of topical steroids for treating eczema or other skin conditions. 

A fun fact about hesperidin: when fermented citrus peels were tested on the skin to see what would happen after UV exposure, collagen production actually INCREASED in the skin cells (whereas, it normally decreases after UV exposure). 

Hesperidin vs. Hesperidin methyl chalcone: structure and function

Pure hesperidin that naturally occurs in citrus fruits has poor solubility in water, which essentially means its absorption and distribution inside the body are minimal. HMC is produced by a simple chemical reaction under alkaline conditions that involves the methylation (i.e. adding methyl groups) of hesperidin. Experiments have demonstrated that such structural changes greatly improve the absorption and transport of related compounds. It is not a surprise that the methylated forms of some flavonoids are shown to have stronger benefits than their unmodified versions. 

What are the benefits of Hesperidin Methyl Chalcone?

  • Anti-dark Circles
  • Antioxidant
  • Barrier Repair
  • Anti-aging

HMC is a common ingredient found in eye creams because of its effective anti-dark circles and anti-puffiness properties. Facial creams and other topical products used to treat sun damage also contain the flavonoid for its anti-melanogenic and anti-inflammatory action, and ability to restore the skin barrier function. Signs of aging on the body and hands (e.g. appearance of dark spots and fine lines) can also be treated with topical creams formulated with HMC, which also offers sun protection, hydration, and pH regulation. There are no known adverse effects or reactivity with other cosmetic ingredients.  

The concentration of HMC in cosmetic products is typically 0.5 to 3%, though, higher concentrations have been tested without reports of adverse effects. One of the most notable benefits is the reduction of bags and puffiness under the eyes by 65% just after 28 days of HMC application.1 For treating dark circles under the eyes, it lowers the filtration rate of capillaries near the skin surface to decrease blood flow through them, thereby, reducing the dark bluish discolouration under the eyes. These functions make HMC a common ingredient found in anti-aging eye creams and facial care. Moreover, the reduction in capillary permeation is also helpful in the treatment of varicose veins. 

A topical cream containing 2% hesperidin is able to stimulate recovery of the barrier function on damaged skin by restoring hydration that is up to 50% of the healthy level in just 2 hours. Furthermore, it reverses the effect of thinning skin and barrier damage from the application of glucocorticoids during the treatment of eczema or other skin conditions by stimulating the proliferation of epidermal cells to increase skin thickness.2,3 It is also able to reverse the effects of declining barrier function associated with aging skin such as dryness and loss of moisture retention. 

Other anti-aging effects of HMC include dark spot treatment by reducing melanin synthesis, and protecting the skin from cell aging due to UV damage – with significant photoprotective effect. Hesperidin also possesses soothing, anti-inflammatory, and anti-redness properties, which are key functions used in cosmetics for treating irritated skin after injury, sun or allergen exposure, and inflammatory pain. An interesting observation on fermented citrus peel is its ability to counteract the processes of UV irradiation on skin cells. While UV normally increases collagen degradation that leads to cell aging, application of the hesperidin-rich fermented peel actually increased collagen synthesis, decreased its degradation, and even reduced the levels of markers typically associated with cell senescence.4

Formulation Consideration

Like all other antioxidants, HMC works best with other antioxidants to provide a synergistic effect. It has strong free radical quenching properties similar to other flavonoids used in cosmetics but requires permeation enhancers to help with skin absorption, otherwise, it would end up drying as a powder on the skin surface. Another characteristic of hesperidin is it’s typically found in bright coloured plants or flowers. As a result, products that contain HMC should have a strong yellow colour, and anything less may be an indication that the product does not contain enough of the ingredient. 

How does Hesperidin Methyl Chalcone work?

The biochemical targets and metabolites of hesperidin are believed to act via a variety of mechanisms depending on the cutaneous function they are regulating. The protective effects of flavonoids generally involve the upregulation of antioxidant activity and downregulation of signaling pathways that lead to apoptosis or inflammation. This is supported by clinical data that demonstrate the potential of HMC to be used in barrier repair, anti-aging, anti-inflammation, and hydration. 

Barrier Repair

Epidermal permeability barrier function is associated with protection against water loss from the skin surface – an important factor in preventing signs of aging. Hesperidin has been shown improve epidermal permeability barrier function by upregulating expression levels of filaggrin and other differentiation-associated mRNA, lipid synthetic enzymes, glutathione reductase mRNA and lipid transport proteins, and stimulate keratinocyte proliferation and β-glucocerebrosidase activity.2 The antioxidant property of hesperidin also reduces oxidative stress in damaged skin to prevent disruptions in the repair process caused by the accumulation of excess free radicals. In fact, it contributes to the acceleration of cutaneous barrier repair. The restorative properties of hesperidin also play a significant role in wound healing by promoting cell migration and vascular formation. These processes involve the activation of tumor growth factor-beta (TGF-β) signaling and vascular endothelial growth factor (VEGF). Inflammatory response is required in the early phases of barrier repair, but excessive inflammation could also delay the process and potentially cause scar formation. According to clinical studies using topical hesperidin, it is able to decrease cytokine expression, including TNF-α, IL-6, and IL-8, and increase expression of antioxidant enzymes.15,16  


Hesperidin attenuates inflammation by interacting with a number of molecules via various signaling pathways. One of the most notable mechanisms of anti-inflammatory action among flavonoids is through inhibition of the p38 mitogen-activated protein kinase (MAPK) pathway, which lowers the expression of cytokines IL-1β, IL-6, IL-8, IL-18, and TNF-α.17,18 In keratinocyte culture models, treatment with hesperidin prior to hydrogen peroxide stimulation was able to reduce over 50% of NF-κB expression and phosphorylated p38 MAPK in comparison to untreated control. A similar anti-inflammatory effect was seen in a lipopolysaccharide-induced cell model. Additionally, hesperidin modulates the inflammatory response by suppressing the PI3K/AKT pathway and increasing the activity of the antioxidant enzyme superoxide dismutase (SOD).19 

When hesperidin is methylated under alkaline conditions to produce HMC, it exhibits similar functions by increasing antioxidant capacity and reducing lipid peroxidation, superoxide anion levels, and mRNA expression of pro-inflammatory factors.5,19,20 It also inhibits edema, neutrophil recruitment, MMP-9 activity, and NF-κB-dependent pro-inflammatory cytokine production.6,7,20 Its analgesic effects and relief of inflammatory-associated pain are attributable to the modulation of TRPV1 receptor activation.5 

Anti-aging, protection against UV damage, and anti-melanogenesis activity

An early sign of aging skin is the formation of dark spots – with chronic UV exposure being a leading cause. It damages our skin through three routes: oxidative stress, DNA fragmentation, and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the antioxidant system in our cells, and its activation stimulates photoprotective effects to prevent UV irradiation-induced apoptosis and inflammation. This involves the upregulation of antioxidant-related gene expression and reduction of ROS levels in epidermal keratinocytes. However, Nrf2 deficiency is accelerated by photoaging and inflammation.21 A decline in UVB-induced damage is seen with hesperidin treatment and the mechanisms behind it involve the regulation of MMP-9 expression, which controls wrinkle formation, and inhibition of MAPK and extracellular signal-regulated kinase (ERK) phosphorylation.10 The ultimate outcome is the reduction of cytokine expression, oxidative stress and DNA damage. 

Another cause of skin pigmentation is increased melanogenesis and melanosome transport. Upregulation of the key proteins that are involved in melanogenesis, including tyrosinase, tyrosinaes-related proteins (TRP), and microphthalmia-associated transcription factor (MITF), is thought to cause signs of aging by increasing melanin production and the appearance of dark spots. Hesperidin has been shown to inhibit the expression of these proteins as well as activate the α-adrenergic receptor, which is involved in melanosome transport in melanocytes.12 Hence, the skin-lightening effect of hesperidin is attributed to its interference with the activity of melanogenesis-associated proteins and melanosome transport.  


The mechanisms hesperidin and HMC utilize to restore skin hydration are not yet known. However, they are closely related to the recovery of the permeability barrier function, which re-establishes an intact skin barrier to prevent moisture loss and restore stratum corneum hydration. 

Clinical trials 



Study Details



3, 10, 30, 100 mg HMC/kg body weight

Mice, n = 6 per group, intraperitoneal administration, in vivo, T = 7-day treatment

HMC reduced inflammation and inflammatory pain by targeting TRPV1 receptor activity, oxidative stress, cytokine production, and NF-κB activity


30-300 mg HMC/kg body weight

Mice, n = 5 per group, intraperitoneal administration 1 h before and 7 h after UVB irradiation, in vivo

HMC at a dose of 300 mg/kg inhibited UVB-induced skin edema, neutrophil recruitment, MMP-9 activity, and oxidative stress. Treatment with HMC lowered production of inflammatory mediators and cytokines. 


1% HMC topical cream (applied 0.5 g)

Mice, n = 5 per group, topical application on dorsal skin, in vivo

HMC neutralized hydroxyl free radicals, and inhibited UVB irradiation-induced skin edema, depletion of antioxidant capacity, lipid peroxidation, and superoxide anion production. It also inhibited cytokine production, particularly TNF-α, IL-1β, IL-6, and IL-10.  


1, 5, and 10 μM hesperidin 

Cell culture (human mesenchymal stem cells, or MSCs), in vitro

Hesperidin inhibited secretion of pro-inflammatory cytokines (e.g. IFN-γ, IL-2, IL-4 and IL-10), and suppressed the expression of p65. 


2% hesperidin

Mice (aged), twice daily for 9 days, topical, in vivo

Hesperidin stimulated epidermal differentiation and improved barrier function in aged skin. The increase in epidermal permeability barrier function may be mediated via Nrf2. 


100 mg hesperidin/mg body weight

Mice, n = 7 per group, orally administered once per day for 12 weeks, in vivo

A significant improvement in UVB-induced wrinkles was observed in mice treated with hesperidin. Epidermal barrier dysfunction and epidermal hypertrophy was inhibited in treated mice. Hesperidin also reduced collagen fiber loss and the expression of pro-inflammatory cytokines and MMP-9 expression. 


50 μM hesperidin

Cell culture (normal human melanocytes and B16F10 melanoma cells), cells were incubated in hesperidin for 3 days, in vitro

Hesperidin strongly inhibited tyrosinase activity, and stimulated Erk1/2 phosphorylation to suppress melanogenic enzymes. 


0.2% hesperidin

Human reconstructed skin model, daily topical application for 14 days

Hesperidin showed a skin lightening effect in the pigmented reconstructed epidermis model. 


0.2 mg/mL HMC

Human skin explants, in vitro, incubated with HMC then subjected to SP stimulation

HMC significantly decreased the proportion of dilated vessels, total vessel area, and IL-8 production. HMC possessed soothing and anti-redness properties. 


Does it penetrate the skin?

Hesperidin which is naturally found in citrus fruits is poorly absorbed and transported in the skin. HMC, which is a modified version, is what you’ll find in cosmetics as it has better absorption. Though, it is still formulated with permeation enhancers to prevent it from drying up as a powder on your skin when you apply it. 



Huang YB, Lee KF, Huang CT, Tsai YH, Wu PC. (2010). The effect of component of cream for topical delivery of hesperidin. Chem Pham Bull. 58(5): 611-614


Hou M, Man M, Man W, Zhu W, Hupe M, Park K, Crumrine D, Elias PM, Man MQ. (2012). Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin. Exp Dermatol. 21(5): 337-340


Man G, Mauro TM, Kim PL, Hupe M, Zhai Y, Sun R, Crumrine D, Cheung C, Nuno-Gonzalez A, Elias PM, Man MQ. (2014). Topical hesperidin prevents glucocorticoid-induced abnormalities in epidermal barrier function in murine skin. Exp. Dermatol. 23(9): 645-651


Bae JT, Ko HJ, Kim GB, Pyo HB, Lee GS. (2012). Protective effects of fermented Citrus unshiu peel extract against ultraviolet-A-induced photoaging in human dermal fibroblasts. Phytother Res PTR. 26(12)” 1851-1856


Pinho-Ribeiro FA, Hohmann MSN, Borghi SM, et. al. (2015). Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: Role of TRPV1, oxidative stress, cytokines and NF-κB. Chemico-Biological Interactions. 223: 88-98. doi: 10.1016/j.cbi.2015.01.011


Martinez RM, Pinho-Ribeiro FA, Steffen VS, et. al. (2015). Hesperidin methyl chalcone inhibits oxidative stress and inflammation in a mouse model of ultraviolet B irradiation-induced skin damage. Journal of Photochemistry and Photobiology B: Biology. 148: 145-153. doi: 10.1016/j.jphotobiol.2015.03.030


Martinez RM, Pinho-Ribeiro FA, Steffen VS, et. al. (2016). Topical formulation containing hesperidin methyl chalcone inhibits skin oxidative stress and inflammation induced by ultraviolet B radiation. Photochemical & Photobiological Sciences. 15: 552. doi: 10.1039/c5pp00467e


Xiao S, Liu W, Bi J, Liu S, Zhao H, Gong N, Xing D, Gao H, Gong M. (2018). Anti-inflammatory effect of hesperidin enhances chondrogenesis of human mesenchymal stem cells for cartilage tissue repair. Journal of Inflammation. 15:14. doi: 10.1186/s12950-018-0190-y


Man G, Mauro TM, Zhai Y, Kim PL, Cheung C, Hupe M, Crumrine D, Elias PM, Man MQ. (2015). Topical Hesperidin Enhances Epidermal Function in an Aged Murine Model. J Invest Dermatol. 135(4): 1184-1187. doi: 10.1038/jid.2014.486


Lee HJ, Im AR, Kim SM, Kang HS, Lee JD, Chae S. (2018). The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via protein kinase (MAPK)-dependent signaling pathways. BMC Complement Altern Med. 18:39. doi: 10.1186/s12906-017-2058-8


Lee HJ, Lee WJ, Chang SE, Lee GY. (2015). Hesperidin, A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation. Int J Mol Sci. 16(8): 18384-18395. doi: 10.3390/ljms160818384


Kim B, Lee JY, Lee HY, Nam KY, Park J, Lee SM, Kim JE, Lee JD, Hwang JS. (2013). Hesperidin Suppresses Melanosome Transport by Blocking the Interaction of Rab27A-Melanophilin. Biomol Therm (Seoul). 21(5): 343-348. doi: 10.4062/biomolther.2013.032


Hernandez-Pigeon H, Garidou L, Galliano MF, Delga H, Aries MF, Duplan H, Bessou-Touya S, Castex-Rizzi N. (2018). Effects of dextran sulfate, 4-t-butylcyclohexanol, pongamia oil and hesperidin methyl chalcone on inflammatory and vascular responses implicated in rosacea. Clin Cosmet Investig Dermatol. 11: 421-429. doi: 10.2147/CCID.S168621


Cosmetic Ingredient Review Expert Panel. (2014). Safety Assessment of Citrus-Derived Ingredients as Used in Cosmetics. Cosmetic Ingredient Review.


Jaetia GC, Rao KVNM. (2017). Topical Application of Hesperidin, a Citrus Bioflavanone Accelerates Healing of Full Thickness Dermal Excision. SM Journal of Nutrition and Metabolism. 3(2): 1021


Wang L, He T, Fu T, et. al. (2018). Hesperidin enhances angiogenesis via modulating expression of growth and inflammatory factor in diabetic foo ulcer in rats. European Journal of Inflammation. 16(2018). doi: 10.1177/2058739218775255


Man MQ, Yang B, Elias PM. (2019). Benefits of Hesperidin for Cutaneous Functions. Evid-Based Complement Alternat Med. 2019: 2676307. doi: 10.1155/2019/2676307


Song W, Wei L, Du Y, Wang Y, Jiang S. (2018). Protective effect of ginsenoside metabolite compound K against diabetic neuropathy by inhibiting NLRP3 inflammasome activation and NF-κB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Int Immunopharmacol. 63: 277-238. doi: 10.1016/j.intimp.2018.07.027


Ferraz CR, Carvalho TT, Manchope MF, et. al. (2020). Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development. Molecules. 25: 762. doi: 10.3390/molecules25030762


Ruiz-Miyazawa KW, Pinho-Ribeiro FA, Borghi SM, Stauengo-Ferrari L, Fattori V, Amaral FA, Teixeira MM, Alves-Filho JC, Cunha TM, Cunha FQ, et. al. (2018). Hesperidin Methylchalcone Suppresses Experimental Gout Arthritis in Mice by Inhibiting NF-κB Activation. J Agric Food Chem. 66: 6269-6280. doi: 10.1021/acs.jafc.8b00959


Saw CLL, Yang AY, Huang MT, et. al. (2014). Nrf2 null enhances UVB-induced skin inflammation and extracellular matrix damages. Cell Biosci. 4:39. doi: 10.1186/2045-3701-4-39