Formulating for Results: The Key Actives Behind Effective Acne Care

Salicylic Acid

• Sebum regulation

Salicylic acid reduces sebum production by inhibiting the AMPK–SREBP‑1 lipid synthesis pathway in human sebocytes (SEB-1), while also promoting apoptotic clearance of overactive sebaceous cells. It decreases inflammation via the NF‑κB pathway, contributing to clearer skin and reduced oiliness.

• Skin Cell turnover

As a keratolytic agent, salicylic acid aids in the breakdown and exfoliation of dead skin cells. It gets within the pores and clears out the dirt that causes acne and blocked pores.

The exfoliating action of salicylic acid promotes skin cell renewal and enhances the penetration of moisturizing substances.

• Skin microbiome

An interesting and novel form is the Supramolecular Salicylic Acid (SSA). It decreases the abundance of acne-associated bacteria such as Ralstonia, Staphylococcus, and Phreatobacter, restoring a healthier microbiota composition similar to that of healthy controls. It slightly increases Cutibacterium levels, a genus linked to skin health, and normalizes the ratio of phyla like Firmicutes, Actinobacteria, and Proteobacteria, indicative of a balanced skin flora. The antimicrobial effects stem from SSA's ability to inhibit pathogenic bacterial colonization, regulate pH, and reduce sebaceous gland secretions, creating an environment favorable for beneficial bacteria. Additionally, SSA impacts the microbiota from the phylum to genus level, suppressing harmful genera and fostering microbial diversity, further underscoring its role in improving skin health. 

• Inflammation

Salicylic acid downregulates proinflammatory cytokines and enzymes in both sebocytes and inflamed skin, through suppression of NF‑κB, COX‑2, and SREBP pathways, and promotes apoptosis of inflammatory cells around acne lesions.

Azelaic Acid

• Sebum regulation

Topical 20% azelaic acid treatments have demonstrated long-term sebostatic effects, helping reduce sebum levels in acne patients. One clinical study reported average sebum reductions from 195 µg/cm² to 150 µg/cm² on the forehead and cheek, persisting even three months post-treatment.

• Skin Cell turnover

Azelaic acid (AZA) is a mild anti-keratinizing agent that reversibly slows keratinocyte growth in a dose- and time-dependent manner. It works by causing mitochondrial swelling and dilation of the rough endoplasmic reticulum in keratinocytes, disrupting their terminal differentiation. This includes delaying filaggrin production and reducing keratohyalin granules and tonofilament bundles, which are key structural elements in mature keratinocytes. AZA also temporarily inhibits DNA, RNA, and protein synthesis, affecting cell proliferation.

• Skin microbiome

The antimicrobial activity of AZA against Propionibacterium acnes and Staphylococcus epidermidis. The mechanism of antimicrobial action is based on the inhibition of the enzyme thioredoxin reductase of bacteria which affects the inhibition of bacterial DNA synthesis that occurs in the cytoplasm.

Azelaic acid (AZA) is an effective acne treatment because it inhibits the growth of acne-causing bacteria like Cutibacterium acnes and Staphylococcus species without causing antibiotic resistance. It works by entering bacterial cells, lowering their internal pH, and blocking essential enzymes needed for DNA and protein synthesis, which weakens or kills the bacteria. AZA is more effective at higher concentrations and acidic pH levels. Studies have shown that AZA not only reduces harmful bacteria but also promotes a healthier balance of skin microbes, increasing beneficial bacteria like lactobacilli. Advanced formulations, such as AZA micro-nanocrystals, have demonstrated even greater antibacterial effects.

Azelaic acid (15% gel) is a common and safe treatment for acne vulgaris, a condition affecting most teenagers and young adults. In a study with 55 acne sufferers using this gel daily for 28 days, researchers analyzed changes in their skin bacteria. They found that acne-affected skin had a different mix of bacteria compared to clear skin. After using the gel, the variety and balance of bacteria in acne areas improved, with a notable increase in beneficial Lactobacillus bacteria. Harmful bacteria like Cutibacterium and Staphylococcus decreased slightly, making the bacterial community on treated acne skin more like that of healthy skin. This suggests that azelaic acid helps restore a healthier skin microbiome in acne patients.

• Inflammation

Azelaic acid (AZA) reduces skin inflammation by blocking several key inflammatory processes. It inhibits the production of reactive oxygen species (ROS) from immune cells and suppresses major inflammatory signaling pathways like NF-κB and MAPK. AZA also activates anti-inflammatory receptors (PPARγ) and lowers the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNFα. Additionally, it decreases the production of inflammatory lipid compounds and inhibits toll-like receptor 2 (TLR2) along with related molecules (KLK5 and LL37), which play important roles in sustaining inflammation in conditions like acne. Together, these actions help calm and control skin inflammation.

Niacinamide

• Sebum regulation

Niacinamide helps reduce excessive sebum production, a study showed that topical 2% niacinamide significantly decreased sebum excretion after 4 weeks of use. Lowering the sebum excretion rate (SER) in Japanese individuals and casual sebum levels (CSL) in Caucasian individuals.

• Skin cell turnover

Research shows niacinamide enhances the biosynthesis of ceramides, fatty acids, and cholesterol, key components of the skin barrier.

• Skin microbiome

Niacinamide positively influences the skin microbiome through its broad-spectrum antimicrobial activity, which includes antibacterial, antifungal, and antiviral effects. It has demonstrated effectiveness in preventing biofilm formation and in reducing pathogens like Escherichia coli, Staphylococcus aureus, and Cutibacterium acnes, a key contributor to acne. Importantly, niacinamide does not kill bacteria directly, instead, it enhances the skin’s innate immune defenses by stimulating the production of antimicrobial peptides (AMPs), such as defensins and cathelicidins in keratinocytes, sebocytes, and neutrophils. These AMPs help maintain a healthy microbial balance on the skin by targeting both Gram-positive and Gram-negative bacteria, as well as fungi and viruses.

It was also found to suppress the growth of several Candida and Cryptococcus spp. strains and to effectively inhibit bacteria like Pseudomonas aeruginosa and Staphylococcus aureus, as well as fungi such as Aspergillus brasiliensis. The antimicrobial action likely occurs through niacinamide binding to DNA, disrupting DNA replication and causing cell division failure. This disruption leads to DNA fragmentation, preventing the growth of harmful microorganisms. 

• Inflammation

Niacinamide exhibits broad and multimodal anti-inflammatory activity, making it highly effective in managing inflammatory skin conditions like acne, as well as systemic inflammatory disorders. It reduces oxidative stress and reactive oxygen species (ROS), which are key triggers of inflammation, and inhibits the secretion of pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6, IL-8, and PGE2) through modulation of NFκB transcription and PARP regulation. Niacinamide influences macrophage and mast cell behavior, stabilizing these immune cells and preventing the release of inflammatory mediators such as histamine and prostaglandins. It also enhances anti-inflammatory markers like IL-10 and MRC-1, while downregulating immune overactivity, including MHC class II expression. Furthermore, it helps prevent keratinocyte and fibroblast senescence, reducing the production of inflammatory molecules associated with the senescence-associated secretory phenotype (SASP). Clinically, niacinamide has shown dose-dependent reductions in skin inflammation markers and offers anti-pruritic benefits by both calming mast cells and restoring the skin barrier via ceramide synthesis. 

Retinoids

• Sebum regulation

Topical retinoids (tretinoin) reduce sebocyte proliferation and influence differentiation via RAR/RXR receptor binding in sebaceous glands, although direct sebum output reduction is less well quantified in vivo, they visibly shrink pores and normalize gland activity.

• Skin cell turnover

Increased epidermal cell renewal improves skin texture, diminishes hyperpigmentation, and enhances collagen and elastin deposition via fibroblast activation and inhibition of matrix metalloproteinases (MMPs).

• Skin microbiome

Topical retinol significantly influences the skin microbiome by restructuring its composition and metabolic activity. Retinol alters microbial gene pathways, especially those involved in vitamin B synthesis and metabolism, promoting the proliferation of microbes enriched in these pathways. It stimulates the production of beneficial microbial metabolites such as apigenin and protocatechuic acid, which have antioxidant and anti-inflammatory properties. Additionally, retinol use leads to increased secretion of acidic microbial metabolites like phenylglyoxylic acid, which help lower skin pH, a critical factor in strengthening the skin barrier and supporting antimicrobial defense. Notably, the microbiome also contributes directly to retinol metabolism, with species like Corynebacterium kefirresidentii and Sericytochromatia sp. aiding in the oxidation of retinol to retinaldehyde, a necessary step for producing active retinoic acid. These microbes, particularly those from the Corynebacterium genus, become more functionally active or enriched after retinol application.

• Inflammation

Modulate inflammation in the skin by directly influencing key components of the innate immune system, such as Toll-like receptors (TLRs). Retinoic acid has been shown to downregulate TLR2 and its co-receptor CD14, leading to a significant reduction, up to 74% in TLR2-induced pro-inflammatory cytokine (IL-6) production in human monocytes. Since TLR2 plays a critical role in initiating immune responses to bacterial components, such as those from Staphylococcus species, its suppression by retinoids may help reduce inflammatory responses in skin conditions like acne and dermatitis. Additionally, retinoic acid signaling is activated downstream of TLR3, which responds to double-stranded RNA from damaged skin or viral infections. In this context, TLR3 activation induces intrinsic RA synthesis that promotes wound healing and hair follicle regeneration, further linking RA to immune-regulated skin repair processes. 

Benzoyl peroxide

• Sebum regulation

Benzoyl peroxide has been shown to decrease metabolism of sebaceous gland cells in humans but whether sebum production is actually decreased is controversial. Free fatty acids decrease in sebum of human patients treated with benzoyl peroxide, presumably because of its antibacterial effect, as bacterial lipases are responsible for production of free fatty acids. 

• Skin cell turnover

Benzoyl peroxide is also believed to have a follicular flushing action.

• Skin microbiome

Benzoyl peroxide (BPO) impacts the skin microbiome by generating reactive oxygen species (ROS) that damage bacterial proteins, effectively reducing the overall bacterial load on the skin, like Cutibacterium acnes and Staphylococcus. This process is enhanced by natural skin lipids and is independent of bacterial structure, allowing BPO to act broadly against many microorganisms. 

• Inflammation

Benzoyl peroxide (BPO) helps reduce skin inflammation primarily by lowering the number of acne-causing bacteria, such as Cutibacterium acnes, which are known to trigger immune responses in the skin. By killing these bacteria through the release of reactive oxygen species (ROS), BPO reduces the production of inflammatory molecules (cytokines). Additionally, BPO has been shown to directly suppress certain inflammatory pathways, such as neutrophil activity and oxidative stress.

References

Bilal H, Xiao Y, Khan MN, Chen J, Wang Q, Zeng Y, Lin X. Stabilization of Acne Vulgaris-Associated Microbial Dysbiosis with 2% Supramolecular Salicylic Acid. Pharmaceuticals (Basel). 2023 Jan 8;16(1):87. doi: 10.3390/ph16010087. PMID: 36678584; PMCID: PMC9864713. 

Brammann C, Müller-Goymann CC. An update on formulation strategies of benzoyl peroxide in efficient acne therapy with special focus on minimizing undesired effects. Int J Pharm. 2020 Mar 30;578:119074. doi: 10.1016/j.ijpharm.2020.119074. Epub 2020 Jan 23. PMID: 31982561.

Decoding the anti-aging effect of retinol in reshaping the human skin microbiome niches. Minyan Gui, Jingmin Cheng, Xueni Lin, Danni Guo, Qi Zhou, Wentao Ma, Hang Yang, Xueqing Chen, Zhao Liu, Lan Ma, Xinhui Xing, Peng Shu, Xiao Liu bioRxiv 2024.06.26.600860; doi: https://doi.org/10.1101/2024.06.26.600860

Draelos ZD, Matsubara A, Smiles K. The effect of 2% niacinamide on facial sebum production. J Cosmet Laser Ther. 2006 Jun;8(2):96-101. doi: 10.1080/14764170600717704. PMID: 16766489.

Endly DC, Miller RA. Oily Skin: A review of Treatment Options. The Journal of Clinical and Aesthetic Dermatology. 2017 Aug;10(8):49-55. PMID: 28979664; PMCID: PMC5605215.

Feng X, Shang J, Gu Z, Gong J, Chen Y, Liu Y. Azelaic Acid: Mechanisms of Action and Clinical Applications. Clin Cosmet Investig Dermatol. 2024 Oct 22;17:2359-2371. doi: 10.2147/CCID.S485237. PMID: 39464747; PMCID: PMC11512533.

Lu J, Cong T, Wen X, Li X, Du D, He G, Jiang X. Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes. Exp Dermatol. 2019 Jul;28(7):786-794. doi: 10.1111/exd.13934. Epub 2019 May 15. PMID: 30972839.

Măgerușan ȘE, Hancu G, Rusu A. A Comprehensive Bibliographic Review Concerning the Efficacy of Organic Acids for Chemical Peels Treating Acne Vulgaris. Molecules. 2023 Oct 22;28(20):7219. doi: 10.3390/molecules28207219. PMID: 37894698; PMCID: PMC10608815. 

Marques C, Hadjab F, Porcello A, Lourenço K, Scaletta C, Abdel-Sayed P, Hirt-Burri N, Applegate LA, Laurent A. Mechanistic Insights into the Multiple Functions of Niacinamide: Therapeutic Implications and Cosmeceutical Applications in Functional Skincare Products. Antioxidants (Basel). 2024 Mar 30;13(4):425. doi: 10.3390/antiox13040425. PMID: 38671873; PMCID: PMC11047333.

Mueller, R. S. (2008). Topical dermatological therapy. In Elsevier eBooks (pp. 546–556). https://doi.org/10.1016/b978-070202858-8.50026-9

Roche FC, Harris-Tryon TA. Illuminating the Role of Vitamin A in Skin Innate Immunity and the Skin Microbiome: A Narrative Review. Nutrients. 2021 Jan 21;13(2):302. doi: 10.3390/nu13020302. PMID: 33494277; PMCID: PMC7909803.

Sauer N, Oślizło M, Brzostek M, Wolska J, Lubaszka K, Karłowicz-Bodalska K. The multiple uses of azelaic acid in dermatology: mechanism of action, preparations, and potential therapeutic applications. Postepy Dermatol Alergol. 2023 Dec;40(6):716-724. doi: 10.5114/ada.2023.133955. Epub 2024 Jan 8. PMID: 38282869; PMCID: PMC10809820.

Szymańska A, Budzisz E, Erkiert-Polguj A. Long-term effect of azelaic acid peel on sebum production in acne. Dermatol Ther. 2022 Jan;35(1):e15186. doi: 10.1111/dth.15186. Epub 2021 Nov 17. PMID: 34731527.

Tanno O, Ota Y, Kitamura N, Katsube T, Inoue S. Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. Br J Dermatol. 2000 Sep;143(3):524-31. doi: 10.1111/j.1365-2133.2000.03705.x. PMID: 10971324.

Yu, Wenxin & Shen, Huchi & Cai, Beilei & Xie, Yuanruo & Wang, Yue & Wang, Jing. (2024). 15% Azelaic acid gel modify the skin microbiota of acne vulgaris. Journal of Dermatologic Science and Cosmetic Technology. 1. 100041. 10.1016/j.jdsct.2024.100041. 

Zasada M, Budzisz E. Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments. Postepy Dermatol Alergol. 2019 Aug;36(4):392-397. doi: 10.5114/ada.2019.87443. Epub 2019 Aug 30. PMID: 31616211; PMCID: PMC6791161.

Zegarska, Barbara & Rudnicka, Lidia & Narbutt, Joanna & Baranska-Rybak, Wioletta & Bergler-Czop, Beata & Chlebus, Ewa & Czarnecka-Operacz, Magdalena & Czuwara, Joanna & Kaszuba, Andrzej & Lesiak, Aleksandra & Nowicki, Roman & Owczarczyk-Saczonek, Agnieszka & Placek, Waldemar & sokolowska-wojdylo, Malgorzata & Szepietowski, Jacek. (2023). Dermocosmetics in the management of acne vulgaris. Recommendations of the Polish Dermatological Society. Part II. Dermatology Review. 110. 593-601. 10.5114/dr.2023.134675.  

Ziklo N, Bibi M, Sinai L, Salama P. Niacinamide Antimicrobial Efficacy and Its Mode of Action via Microbial Cell Cycle Arrest. Microorganisms. 2024 Aug 2;12(8):1581. doi: 10.3390/microorganisms12081581. PMID: 39203423; PMCID: PMC11356291.