Pigmentation and Melasma: Copper, Iron, ET-1 and Light

Pigmentation is where the copper–iron axis shows on the surface. This post applies the mechanisms set out in the companion post, Skin Longevity From the Inside Out, to melasma, sun spots and pigmentation after inflammation or procedures. Endothelin-1 (ET-1) and blue light are explained in full there; here they are applied to pigment.

Melasma through the copper, iron and ET-1 lens

Of the three, endothelin-1 has the strongest melasma-specific evidence. The iron data point, surprisingly, towards low body iron rather than overload, and copper shows no consistent difference.

How ET-1 gets raised in the skin's blood vessels

In melasma, much of the ET-1 that drives pigment comes from the small blood vessels under the patch (Regazzetti 2015; Park 2015). Each step from the copper–iron axis to that vascular ET-1 has its own evidence:

1. Iron accumulation and copper shortfall create free iron and leaking mitochondria. Without enough copper, ceruloplasmin cannot move iron out of tissue, and Complex IV leaks superoxide; free iron then turns hydrogen peroxide into hydroxyl radicals through the Fenton reaction (see the skin longevity post).
2. Oxidative stress switches on ET-1 in vessel cells. Reactive oxygen species increase ET-1 production by endothelial cells (Kähler 2002), and people with iron overload from β-thalassaemia have higher baseline ET-1 (Viprakasit 2002).
3. The brake on ET-1 is lost. Nitric oxide normally suppresses ET-1: blocking endothelial nitric oxide raised baseline ET-1 three- to fourfold (Kourembanas 1993). Superoxide destroys nitric oxide, turning it into peroxynitrite, and copper deficiency impairs nitric oxide–driven relaxation while making vessels contract more strongly to ET-1 (Schuschke 2000; Majewski 2019).
4. ET-1 then feeds itself. ET-1 switches on NADPH oxidase to make more superoxide, which consumes more nitric oxide and drives more ET-1 (arteriole study).

UVB triggers ET-1 directly through DNA damage, and inflammation adds more free radicals, but these are normally self-limiting responses. This post's hypothesis is that iron accumulation and copper shortfall are what keep vascular ET-1 running out of control, by feeding the oxidative loop that ET-1 itself amplifies. Each link above is shown; the whole chain has not yet been measured in one study. The study needed would compare ET-1 in melasma skin and blood between people with and without iron accumulation or copper shortfall.

Melasma behaves like localised photoageing, which is where iron fits. Lesional skin shows moderate-to-severe solar elastosis in 93% of patients, basement-membrane damage and extra blood vessels (Kwon 2016). UV-stressed, senescent dermal fibroblasts release pigment-stimulating signals such as stem cell factor and hepatocyte growth factor (Miao 2025). That is the same terrain as the UVA → free iron → oxidative stress → senescent fibroblast pathway in the skin longevity post, and oxidative stress raises ET-1 in vessel cells. Three further findings tighten the link. People with melasma carry more oxidative stress: in 50 patients, serum malondialdehyde (a lipid-peroxidation marker) and antioxidant enzymes were higher than in controls, and malondialdehyde rose with severity (Choubey 2017). Melanin itself loads cells with iron: in keloid tissue, excess melanin drove iron build-up in melanocytes, keratinocytes and fibroblasts, and the iron chelator deferoxamine reversed the resulting scarring response (Keloid study 2025). And UVB damages human melanocytes partly through ferroptosis, the iron-dependent form of cell death (2025). So a local iron–ET-1 contribution is biologically coherent and worth testing; it simply has not been tested yet.

Blue light and melasma. Blue light around 415 nm falls in the band iron-containing heme compounds absorb and also switches on lasting pigment through OPN3 in skin types III and above (see "Blue light sits in the iron band" in the skin longevity post). That helps explain why visible light, not just UV, worsens melasma.

Vitamin D. People with melasma had lower 25(OH)D in observational studies (Skin 2023), but no trial has shown that raising vitamin D improves melasma, and sun avoidance alone could explain the gap. Inflammation offers another explanation: raised active vitamin D (1,25-dihydroxyvitamin D) speeds the breakdown of stored 25(OH)D (Clements 1992), and inflammation lowers 25(OH)D directly, by 40% within two days of surgery in one study (Reid 2011). Given the oxidative stress measured in melasma, a low 25(OH)D may partly reflect that, so read it alongside active vitamin D, PTH, calcium and CRP before calling it deficiency. I have not found a study measuring active vitamin D in melasma.

Mitochondrial dysfunction and pigment

Mitochondria do more than power pigment cells; their state helps set how much pigment is made.

• Pigmented lesions run on failing mitochondria. Measuring cell metabolism non-invasively in living skin, researchers found reduced oxidative phosphorylation (mitochondrial energy production) in solar lentigo lesions compared with adjacent normal skin, alongside markers of senescence (2025 study).
• Melasma skin is more senescent. Melasma has a more prominent senescent phenotype than surrounding photoaged skin, and senescence is marked by oxidative stress, DNA damage and mitochondrial dysfunction; UV-induced early senescence can trigger and perpetuate melanin production (melasma fibroblast study 2022; review). In 130 patients, melasma was linked to lower antioxidant levels, and tyrosinase activity was higher in lesional than non-lesional skin (Katiyar 2024).
• Mitochondrial shape controls melanin output. In pigment cells, blocking the mitochondrial fission protein Drp1 increased melanin, while fragmenting mitochondria suppressed it by raising mitochondrial ROS and ERK signalling, which breaks down MITF, the master pigment switch (Kim 2014). This is cell work, but it shows mitochondria directly tune pigment production.
• Blue light hits mitochondria. Blue light, but not green, red or infrared, caused mitochondrial oxidative stress in live skin (Nakashima 2017, in the skin longevity post).

The skin longevity post sets out what keeps mitochondria working: copper for Complex IV, retinol to feed the electron transport chain, magnesium to make ATP usable, and keeping free iron out of mitochondria. Whether correcting these changes pigmentation has not been tested.

Sun spots and air pollution

In 400 German women aged 70–80, higher exposure to traffic soot and particles was associated with 20% more pigment spots on the forehead and cheeks (Vierkötter 2010); the finding was later replicated in Caucasian and Asian cohorts (review). Polycyclic aromatic hydrocarbons on the particles act through the aryl hydrocarbon receptor, which also stimulates melanocytes (MDedge).

Pigmentation after inflammation and procedures

After flares. Eczema, psoriasis and contact dermatitis commonly leave post-inflammatory hyperpigmentation; it is more marked and longer-lasting in darker skin types, and UV makes it worse (Kaufman 2018; Mar 2024). The companion post on inflammatory skin conditions covers this in more detail.

After procedures. The idea that iron-loaded skin and high ET-1 make lasers and microneedling more likely to cause post-inflammatory hyperpigmentation is a reasonable hypothesis that has not been tested. What has been tested surprises many clinicians: in a randomised trial of 100 CO2-laser patients, pretreatment with hydroquinone plus tretinoin, or glycolic acid, did not reduce post-laser hyperpigmentation compared with no pretreatment (West & Alster 1999). Strict sun avoidance before and after, appropriate energy settings for skin type, and early treatment if pigmentation appears have better support.

What this means in practice

• Sun avoidance does not create healthy skin. Regular, low-dose sunlight strengthens the barrier, builds the skin's own melanin and thickened outer layer, and supplies vitamin D and nitric oxide (see "Avoiding the sun does not create healthy skin" in the skin longevity post). With pigmentation, the aim is to protect the affected areas, not to avoid the sun: shield the face and pigmented patches from UV and visible light, and get short, regular, non-burning sun on the arms and legs, timed outside peak midday UV except for brief vitamin D exposure.
• Block visible light as well as UV. In a double-blind trial of 68 melasma patients, a sunscreen with iron oxide pigment (which absorbs visible light) plus hydroquinone improved MASI scores 15% more than a UV-only SPF 50 (Castanedo-Cazares 2014); a second trial showed fewer relapses. The iron oxide here is an inert pigment on the skin surface, not iron entering tissue.
• Tranexamic acid targets the vascular side. Across 22 randomised trials, it reduced melasma severity, oral most of all, with high heterogeneity between studies (Calacattawi 2024). Oral use needs screening for clotting risk.
• Check ferritin both ways, and never on its own. Given the low-iron findings in melasma, test before assuming overload, and treat true deficiency. Ferritin rises with inflammation and infection and leaks from damaged cells, which can make a low-iron person look normal and an inflamed person look overloaded. The WHO advises measuring ferritin alongside CRP and α1-acid glycoprotein (AGP), and in someone with inflammation, a ferritin below 70 µg/L may already indicate deficiency, against below 15 µg/L in healthy adults (WHO 2020). Add transferrin saturation: high ferritin with high saturation points to true iron loading; high ferritin with low saturation points to inflammation trapping iron in storage.
• Go carefully with heat. Energy devices that inflame or heat the dermis can flare melasma; conservative settings and test areas are sensible, and the ET-1 pathway gives a plausible reason why.
• Watch this space. Topical endothelin-B receptor blockers are a stated research target (Regazzetti 2015).

References

Melasma: ET-1, iron and copper

• Esposito ACC et al. Endothelin-1 expression in facial melasma. Clin Cosmet Investig Dermatol. Link
• Regazzetti C et al. Endothelial cells promote pigmentation through endothelin receptor B activation. J Invest Dermatol 2015. Link
• Park JY et al. UV-exposed vascular endothelial cells and melanogenesis via endothelin-1. 2015. Link
• Prakash et al. Serum ferritin in melasma: a case-control study. 2021. Link
• Goodarzi A et al. Iron status in melasma. 2020. Link
• Behrangi E et al. Serum iron and ferritin in melasma. 2015. Link
• Serum copper and melasma in 200 Iraqi participants. JAMPS 2024. Link
• Rani et al. Serum copper in hyperpigmentary disorders. 1978. Link
• Rostami Mogaddam M et al. Serum zinc in melasma. 2018. Link
• Serum zinc in melasma. 2020. Link

Melasma as localised photoageing

• Kwon SH et al. Melasma: updates and perspectives on photoageing changes in lesional skin. 2016. Link
• Miao et al. Senescent fibroblasts and pigment-stimulating signals. Biology 2025. Link
• Choubey V et al. Role of oxidative stress in melasma. Int J Dermatol 2017. Link
• Melanin-driven iron accumulation in keloid tissue, reversed by deferoxamine. 2025. Link
• UVB damage to human melanocytes through ferroptosis. Photochem Photobiol Sci 2025. Link
• Vitamin D status in melasma. Skin 2023. Link
• Clements MR et al. The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin Endocrinol 1992. Link
• Reid D et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am J Clin Nutr 2011. Link

Mitochondrial dysfunction and pigment

• Non-invasive measurement in solar lentigo: mitochondrial dysfunction and senescence. Int J Mol Sci 2025. Link
• Morphology, growth and gene expression of fibroblasts from melasma skin. 2022. Link
• Oxidative stress in the pathogenesis of chloasma: a review. Dovepress. Link
• Katiyar S et al. Markers of oxidative stress and tyrosinase activity in melasma patients. Curr Protein Pept Sci 2024. Link
• Kim ES et al. Mitochondrial dynamics regulate melanogenesis through proteasomal degradation of MITF via ROS-ERK activation. Pigment Cell Melanoma Res 2014. Link
• Nakashima Y et al. Blue light-induced oxidative stress in live skin. Free Radic Biol Med 2017. Link

Sun spots and air pollution

• Vierkötter A et al. Airborne particle exposure and extrinsic skin aging. J Invest Dermatol 2010. Link
• Oxidative contribution of air pollution to extrinsic skin ageing. Free Radic Biol Med 2020. Link
• Traffic soot may be major cause of skin aging. MDedge. Link

Pigmentation after inflammation and procedures

• Kaufman BP et al. Postinflammatory hyperpigmentation: epidemiology, clinical presentation, pathogenesis and treatment. Am J Clin Dermatol 2018. Link
• Mar K et al. Treatment of post-inflammatory hyperpigmentation in skin of colour: a systematic review. J Cutan Med Surg 2024. Link
• West TB, Alster TS. Effect of pretreatment on the incidence of hyperpigmentation following CO2 laser resurfacing. Dermatol Surg 1999. Link

Treatment and testing

• Castanedo-Cazares JP et al. Near-visible light and UV photoprotection in the treatment of melasma: a double-blind randomized trial. Photodermatol Photoimmunol Photomed 2014. Link
• Calacattawi R et al. Tranexamic acid for melasma: systematic review and meta-analysis of 22 randomised trials. 2024. Link
• World Health Organization. Guideline on use of ferritin concentrations to assess iron status in individuals and populations. 2020. Link