Pathogenetic mechanisms of skin hyperpigmentation: A cohort prospective study

Background. Acquired skin hyperpigmentation has a pathogenetic origin in the increased activity of melanocytes and melanin synthesis, as well as its saturation of neighboring keratinocytes. However, the issue of molecular mechanisms of occurrence is not fully disclosed. Maintenance of increased cellular metabolism and synthetic process during melanogenesis requires a large amount of energy and plastic substrates to build cell membranes. Thus, the gas transport function of blood erythrocytes and levels of lipoproteins of different classes in serum in patients with hyperpigmentation seemed relevant to study in order to identify their possible contribution to the pathogenesis of this condition.

Objectives. To identify systemic changes in blood parameters in patients with acquired skin hyperpigmentation before and after treatment as well as to assess their possible contribution to the mechanisms of skin hyperpigmentation formation.

Methods. A cohort prospective study included 50 women aged 42–44 years, living in Rostov-on-Don, who sought medical care at the clinic of the Davinci Group LLC. The study group, 25 patients with a mean age of 41.88 ± 1.45 years, had hyperpigmentation, and the control group of individuals with a mean age of 41.84 ± 1.57 years did not have hyperpigmentation, having come to the clinic for cosmetic purposes. The laboratory stage of the study was conducted in a laboratory of the Department of General and Clinical Biochemistry No. 1 of the Rostov State Medical University of the Ministry of Health of the Russian Federation. Two groups (25 people each) were formed according to the criterion of presence or absence of hyperpigmentation. The target parameters of the study were screening of lipid and cholesterol profiles in blood serum, and assessment of the 2,3-diphosphoglycerate level and products of carbohydrate metabolism in erythrocytes. Total cholesterol, triacylglycerides, and high-density lipoproteins were determined by enzymatic colorimetric method using a Chronolab AG diagnostic kits (Chronolab, Switzerland). The concentration of low-density lipoproteins was determined by turbidimetric method, while the concentration of very low-density lipoproteins was calculated with the “concentration of triacylglycerides / 5” formula. The level of 2,3-diphosphoglycerate was measured by non-enzymatic analysis in trichloroacetic acid filtrate of hemolyzed erythrocytes, while the concentration of lactate and pyruvate was determined using an automated biochemical analyzer VitaLine-200 (Vital Development Corporation, Russia). The collected database was analyzed using descriptive and comparative statistical analysis in Statistica 12.0 software package (StatSoft, USA). Differences were considered statistically significant at p < 0.05.

Results. The study of metabolic features of lipoprotein metabolism of different classes in patients with hyperpigmentation indicated an increase in the levels of certain classes of lipoproteins compared to the control group. A statistically significant increase in the concentration of total cholesterol, triacylglycerides, along with a tendency to a decrease in high-density lipoproteins were observed. The median value of the total cholesterol level in the blood of patients with hyperpigmentation was found to be significantly higher than in the control group by 22.2% relative to the control (p = 0.003), with a statistically significant increase in the median concentration of triacylglycerides relative to the control (p = 0.032). Women with clinical manifestations of skin hyperpigmentation showed a 58.5% decrease in pyruvate concentration compared to the control group (p = 0.029), whereas the lactate level was found to be 193.9% higher than in the control group (p < 0.001). The lactate level in the study group statistically significantly increased after treatment compared to the values before treatment thus approaching the control values (p = 0.609). Meanwhile, the median concentration of 2,3-diphosphoglycerate in the study group before treatment was higher compared to the median in the control group, albeit the difference was not statistically significant (p = 0.139).

Conclusion. Patients with hyperpigmentation were found to have statistically significantly increased levels of certain classes of lipoproteins, such as triacylglycerides, and total cholesterol in the blood. These changes indicate an ongoing need of cells for synthesis of membrane lipids and maintenance of increased cellular metabolism, which is required for increased regeneration of the epidermis. The obtained data reveal a change in the priority of oxygen distribution in cellular structures and tissues, followed by a significant increase in the level of lactate and the development of local tissue hypoxia.

1. Muller B, Flament F, Jouni H, Sextius P, Tachon R, Wang Y, Wang H, Qiu H, Qiu J, Amar D, Delaunay C, Jablonski NG, Passeron T. A Bayesian network meta-analysis of 14 molecules inhibiting UV daylight-induced pigmentation. J Eur Acad Dermatol Venereol. 2024;38(8):1566– 1574. https://doi.org/10.1111/jdv.19910

2. Lambert KA, Clements CM, Mukherjee N, Pacheco TR, Shellman SX, Henen MA, Vögeli B, Goldstein NB, Birlea S, Hintzsche J, Caryotakis G, Tan AC, Zhao R, Norris DA, Robinson WA, Wang Y, VanTreeck JG, Shellman YG. SASH1 S519N Variant Links Skin Hyperpigmentation and Premature Hair Graying to Dysfunction of Melanocyte Lineage. J Invest Dermatol. 2025;145(1):144–154.e3. https://doi.org/10.1016/j.jid.2024.04.027

3. Tisack A, Mohammad TF. Drug-Induced Pigmentation: A Review. Drugs. 2024;84(9):1071–1091. https://doi.org/10.1007/s40265-024-02062-z

4. Lee KW, Cho YY, Kim KD. RCHY1 and OPTN: an E3-ligase and an autophagy receptor required for melanophagy, respectively. Autophagy. 2024;20(10):2352–2353. https://doi.org/10.1080/15548627.2024.237 0058

5. da Rosa GP, Vide J, Azevedo F, Mota A. Skin hyperpigmentation heralding an ectopic adrenocorticotropic hormone production. J Dermatol. 2024;51(8):e251–e252. https://doi.org/10.1111/1346-8138.17323

6. Sharma AN, Kincaid CM, Mesinkovska NA. The Burden of Melasma: Race, Ethnicity, and Comorbidities. J Drugs Dermatol. 2024;23(8):691– 693. https://doi.org/10.36849/JDD.8233

7. Thawabteh AM, Jibreen A, Karaman D, Thawabteh A, Karaman R. Skin Pigmentation Types, Causes and Treatment-A Review. Molecules. 2023;28(12):4839. https://doi.org/10.3390/molecules28124839

8. Doolan BJ, Gupta M. Melasma. Aust J Gen Pract. 2021;50(12):880–885. https://doi.org/10.31128/AJGP-05-21-6002

9. Shenoy A, Madan R. Post-Inflammatory Hyperpigmentation: A Review of Treatment Strategies. J Drugs Dermatol. 2020 Aug 1;19(8):763–768. https://doi.org/10.36849/JDD.2020.4887

10. Mar K, Maazi M, Khalid B, Ahmed R, Wang OJE, Khosravi-Hafshejani T. Prevention of Post-Inflammatory Hyperpigmentation in Skin of Colour: A Systematic Review. Australas J Dermatol. 2025;66(3):119–126. https://doi.org/10.1111/ajd.14432

11. Wakamatsu K, Ito S. Recent Advances in Characterization of Melanin Pigments in Biological Samples. Int J Mol Sci. 2023;24(9):8305. https://doi.org/10.3390/ijms24098305.

12. Wiriyasermkul P, Moriyama S, Nagamori S. Membrane transport proteins in melanosomes: Regulation of ions for pigmentation. Biochim Biophys Acta Biomembr. 2020;1862(12):183318. https://doi.org/10.1016/j.bbamem.2020.183318

13. Wang F, Ma W, Fan D, Hu J, An X, Wang Z. The biochemistry of melanogenesis: an insight into the function and mechanism of melanogenesis-related proteins. Front Mol Biosci. 2024;11:1440187. https://doi.org/10.3389/fmolb.2024.1440187

14. Zhou S, Zeng H, Huang J, Lei L, Tong X, Li S, Zhou Y, Guo H, Khan M, Luo L, Xiao R, Chen J, Zeng Q. Epigenetic regulation of melanogenesis. Ageing Res Rev. 2021;69:101349. https://doi.org/10.1016/j.arr.2021.101349

15. Longo DL, Stefania R, Aime S, Oraevsky A. Melanin-Based Contrast Agents for Biomedical Optoacoustic Imaging and Theranostic Applications. Int J Mol Sci. 2017;18(8):1719. https://doi.org/10.3390/ijms18081719

16. Malik S, Le L, Boissy RE, Brideau-Andersen A, Sondergaard B. Botulinum neurotoxin type DC (BoNT/DC) cleavage of VAMP3 reduces melanin production in melanocytes. Toxicon. 2025;261:108372. https://doi.org/10.1016/j.toxicon.2025.108372

17. Naik PP, Farrukh SN. Influence of Ethnicities and Skin Color Variations in Different Populations: A Review. Skin Pharmacol Physiol. 2022;35(2):65–76. https://doi.org/10.1159/000518826

18. Wang Y, Xiong B, Xing S, Chen Y, Liao Q, Mo J, Chen Y, Li Q, Sun H. Medicinal Prospects of Targeting Tyrosinase: A Feature Review. Curr Med Chem. 2023;30(23):2638–2671. https://doi.org/10.2174/0929867329 666220915123714

19. Babbush KM, Babbush RA, Khachemoune A. The Therapeutic Use of Antioxidants for Melasma. J Drugs Dermatol. 2020;19(8):788–792. https://doi.org/10.36849/JDD.2020.5079

20. Bychkova NYu, Lemytskaya VE, Sokolovskaya JuA, Zhukova OV, Kasikhina EI. Review of modern melasma treatment methods. Meditsinskiy Sovet. 2024;18(14):108–116 (In Russ.). https://doi.org/10.21518/ms2024-349

21. Ikonnikova EV, Korchazhkina NV, Stenko AG. Laser technologies in the correction of nonneoplastic melanin hyperpigmentation of the skin. Russian Journal of the Physical Therapy, Balneotherapy and Rehabilitation. 2018;17(1):19–24 (In Russ.). http://dx.doi.org/10.18821/1681-3456-2018-17-1-19-24.

22. Zhang C, Wu T, Shen N. Effect of platelet-rich plasma combined with tranexamic acid in the treatment of melasma and its effect on the serum levels of vascular endothelial growth factor, endothelin-1 and melatonin. Pak J Med Sci. 2022;38(8):2163–2168. https://doi.org/10.12669/pjms.38.8.6786

23. Espósito ACC, Cassiano DP, da Silva CN, Lima PB, Dias JAF, Hassun K, Bagatin E, Miot LDB, Miot HA. Update on Melasma-Part I: Pathogenesis. Dermatol Ther (Heidelb). 2022;12(9):1967–1988. https://doi.org/10.1007/s13555-022-00779-x

24. Svirshchevskaia EV, Matushevskaia EV. Role of lipids in skin barrier properties. Russian Journal of Clinical Dermatology and Venereology. 2019;18(3):360–365 (In Russ.). https://doi.org/10.17116/klinderma201918031360

25. Baker P, Huang C, Radi R, Moll SB, Jules E, Arbiser JL. Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties. Cells. 2023;12(23):2745. https://doi.org/10.3390/cells12232745

26. Iranmanesh B, Khalili M, Mohammadi S, Amiri R, Aflatoonian M. The efficacy of energy-based devices combination therapy for melasma. Dermatol Ther. 2021;34(3):e14927. https://doi.org/10.1111/dth.14927

27. Shah SD, Aurangabadkar SJ. Laser Toning in Melasma. J Cutan Aesthet Surg. 2019;12(2):76–84. https://doi.org/10.4103/JCAS.JCAS_179_18

28. Baltabaev MK, Kurbanova DCh. Optimization of methods of treatment of melasma (chloasma). Scientific Review Medical Sciences. 2023;3:73– 79 (In Russ.). http://dx.doi.org/10.17513/srms.1345

29. Dyce BJ, Bessman SP. A rapid nonenzymatic assay for 2,3-DPG in multiple specimens of blood. Arch Environ Health. 1973;27(2):112–115. https://doi.org/10.1080/00039896.1973.10666331

30. Pandya AG, Hynan LS, Bhore R, Riley FC, Guevara IL, Grimes P, Nordlund JJ, Rendon M, Taylor S, Gottschalk RW, Agim NG, Ortonne JP. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol. 2011;64(1):78–83, 83.e1–2. https://doi.org/10.1016/j.jaad.2009.10.051

31. Alieva AS, Usova EI, Zvartau NE, Shlyakhto EV. Implementation study to introduce clinical guidelines on lipid metabolism disorders into routine practice: results of the first stage. Russian Journal of Cardiology. 2024;29(1):5724 (In Russ.). https://doi.org/10.15829/1560-4071-2024-5724

32. Ezhov MV, Sergienko IV, Kukharchuk VV. Clinical guidelines for lipid disorders 2023. What’s new. Atherosclersis and dyslipidemias. 2023;3(52):5–9 (In Russ.). https://doi.org/10.34687/2219-202. JAD.2023.03.0002

33. Sochorová M, Audrlická P, Červená M, Kováčik A, Kopečná M, Opálka L, Pullmannová P, Vávrová K. Permeability and microstructure of cholesterol-depleted skin lipid membranes and human stratum corneum. J Colloid Interface Sci. 2019;535:227–238. https://doi.org/10.1016/j.jcis.2018.09.104

34. Bonté F, Girard D, Archambault JC, Desmoulière A. Skin Changes During Ageing. Subcell Biochem. 2019;91:249–280. https://doi.org/10.1007/978-981-13-3681-2_10

35. Khabarov VN. Kollagen, elastin, gialuronovaya kislota v molekulyarnoi kosmetologii [Collagen, elastin, hyaluronic acid in molecular cosmetology]. Moscow: GEOTAR-Media; 2024. 21 p. (In Russ.). https://doi.org/10/33029/9704-7993-3-KEG-2024-1-368

36. Cayo A, Segovia R, Venturini W, Moore-Carrasco R, Valenzuela C, Brown N. mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership. Int J Mol Sci. 2021;22(15):8149. https://doi.org/10.3390/ijms22158149

37. Narzt MS, Pils V, Kremslehner C, Nagelreiter IM, Schosserer M, Bessonova E, Bayer A, Reifschneider R, Terlecki-Zaniewicz L, Waidhofer-Söllner P, Mildner M, Tschachler E, Cavinato M, Wedel S, Jansen-Dürr P, Nanic L, Rubelj I, El-Ghalbzouri A, Zoratto S, Marchetti-Deschmann M, Grillari J, Gruber F, Lämmermann I. Epilipidomics of Senescent Dermal Fibroblasts Identify Lysophosphatidylcholines as Pleiotropic Senescence-Associated Secretory Phenotype (SASP) Factors. J Invest Dermatol. 2021;141(4S):993–1006.e15. https://doi.org/10.1016/j.jid.2020.11.020

38. Kruglikov IL, Zhang Z, Scherer PE. Skin aging: Dermal adipocytes metabolically reprogram dermal fibroblasts. Bioessays. 2022;44(1):e2100207. https://doi.org/10.1002/bies.202100207

39. Tlish MM, Shavilova ME. Modern possibilities of a supporting therapy and correction of post-inflammatory skin changes in patients with acne. Vestnik Dermatologii i Venerologii. 2021;97(4):92–99 (In Russ.). https://doi.org/10.25208/vdv1241