Theoretical and potential combined use of salicylic acid, azelaic acid, and lactic acid in acne care

SA

SA is a lipophilic BHA that can penetrate the hair follicles, dissolving sebum and comedones, thereby reducing acne formation. In addition, SA reduces the production of pro-inflammatory mediators by inhibiting prostaglandin synthesis and decreasing the release activity of cyclooxygenase and lipoxygenase in tissues. It also inhibits the activated protein kinase/sterol regulatory element-binding protein 1 (AMPK/SREBP-1) pathway in sebocytes, thus decreasing sebum secretion. Moreover, SA exhibits inhibitory effects on Cutibacterium acnes and staphylococci.^10,11

Compared to LA and AZA, SA, due to its lipophilic nature, can cross the stratum corneum barrier and penetrate deeper into the hair follicles, promoting the dissolution of comedones. It also exhibits significant anti-inflammatory activity without causing inflammation and is not photosensitive, allowing for daytime use. In addition, SA absorbs ultraviolet (UV)B, reducing UV-induced skin damage, which is why SA and its derivatives are used in sunscreen formulations. However, due to its limited penetration through the stratum corneum, its efficacy in improving severely UV-damaged skin is weaker.

When used at concentrations of 2% or higher, SA may cause localized skin reactions such as peeling, dryness, or mild irritation, particularly in individuals with sensitive skin.¹² These effects are primarily due to its potent keratolytic activity and follicular penetration. Although generally well-tolerated, extensive or prolonged use may increase the risk of systemic absorption and salicylate toxicity. As such, SA is classified as a Category C drug by the U.S. Food and Drug Administration and is contraindicated during pregnancy, lactation, or in individuals with known hypersensitivity to aspirin. Its lipophilic nature makes it, especially suitable for oily and acne-prone skin types.¹³

AZA

AZA is a saturated dicarboxylic acid with two carboxyl groups in its structure (whereas SA and LA each have one carboxyl group). This structure gives AZA unique physical and chemical properties. AZA inhibits tyrosinase activity, reducing melanin production, making it advantageous in skin lightening and the treatment of hyperpigmentation, particularly in melasma and other pigmented skin disorders, a feature less prominent in SA and LA.^14,15 AZA also exhibits antibacterial activity by inhibiting bacterial protein synthesis, particularly against C. acnes and Staphylococcus epidermidis, with no resistance development. In addition, AZA has anti-inflammatory, antioxidant, keratolytic, sebum-reducing, and anti-proliferative effects.

Toxicological studies have demonstrated that AZA lacks acute or chronic toxicity, mutagenicity, or teratogenicity and is considered safe for use during pregnancy and lactation, making it a favorable therapeutic option for individuals of reproductive age. Its broad safety profile and multifaceted dermatologic benefits render it suitable for all skin types, particularly oily or hyperpigmented skin.¹⁶

Although generally well-tolerated, AZA may induce mild and transient local adverse reactions. Approximately 5–10% of patients report sensations of burning, stinging, tightness, or erythema at the site of application. These effects are typically self-limiting and tend to subside within the 1^st few weeks of treatment, without requiring discontinuation in most cases.¹²

LA

LA is a popular AHA and a water-soluble substance found in many household items and prescription medications. It exists in two stereoisomers: D-LA and L-LA, with L-LA (levorotatory LA) having biological significance. Compared to SA and AZA, LA, as a natural moisturizing factor and a product of glycolysis, is a skin-homologous organic acid with a milder action. It plays a key role in various cellular processes through its monocarboxylate transporters (MCTs) and G protein-coupled receptor 81 (GPR81). LA is essential for energy transfer within and between tissues and plays a crucial role in the overall energy metabolism of organisms. In addition, LA and its salts can modulate inflammatory responses and promote immune tolerance, while exhibiting broad-spectrum antibacterial and antimicrobial activity against both Gram-positive and Gram-negative bacteria. Furthermore, LA significantly increases ceramide content, optimizes ceramide quality, and promotes the formation of a better lipid barrier. L-LA also acts as a signaling molecule for collagen synthesis and regeneration and as an angiogenesis promoter, accelerating wound healing.^17,18

LA is generally well-tolerated across all skin types, particularly beneficial for dry or sensitive skin due to its moisturizing and barrier-repair properties. However, when used at concentrations around 10% – a level commonly employed in skin sensitivity testing – it may cause transient sensations of stinging or itching within minutes of application. These effects are typically short-lived and may lead to mild dryness at the site of contact but do not usually result in erythema, desquamation, or blistering. Such reactions reflect the temporary disruption of the stratum corneum without inducing significant inflammatory responses.¹⁹

Synergistic effect of keratin regulation

Although SA, AZA, and LA can all exfoliate, their mechanisms are not the same. As a lipophilic agent, SA causes desquamation by the dissolution of intercellular cement material.²⁰ SA also extracts desmosomal proteins including desmogleins. As a result of this action, the cohesion of epidermal cells is lost, leading to exfoliation.¹⁹ SA does not affect mitotic activity in human epidermal cells.²⁰ The use of SA on human skin causes thinning of the corneal layer without any change in the thickness of the epidermis.²¹

AZA, as an antikeratinizing agent, is a competitive inhibitor of important mitochondrial respiratory chain enzymes, reducing adenosine triphosphate (ATP) synthesis through enzyme inhibition, thereby attenuating ATP-dependent kinases such as the fibroblast growth factor receptor 2b (FGFR2b)-signaling cascade. AZA has a reversibly antiproliferative effect on keratinocytes, affecting the early and final regulation of epidermal differentiation. The antiproliferative effect of AZA is associated with reduced deoxyribonucleic acid (DNA) synthesis, mitochondrial damage, and expansion of the rough endoplasmic reticulum. In addition, AZA decreases the expression of filaggrin in the granular layer.²²

LA can remove keratin through three pathways: (1) LA, acting as a proton donor, can activate the cell membrane transient receptor potential vanilloid 3 (TRPV3) channel, causing calcium influx, accelerating keratinocyte apoptosis, and promoting keratin shedding.²³ (2) LA can chelate Ca2+, disrupting the conjugated structure of corneodesmosomes, making them more susceptible to degradation, weakening the adhesion of corneodesmosomal calcium-binding proteins, and accelerating desquamation. (3) By activating desquamation-related enzymes: LA can lower the pH of the epidermis, activating steroid sulfatase and serine proteases, accelerating corneodesmosome degradation, and facilitating the shedding of the aged stratum corneum.²⁴ AHAs have been demonstrated to regulate the skin’s natural shedding process. Consequently, consistent use of AHAs leads to a balanced rate of skin exfoliation, making skin shedding less noticeable or even unnoticeable to the user after 2–3 weeks.²⁵

SA, AZA, and LA exhibit effective exfoliating properties, each contributing to the improvement of keratinization disorders while retaining their distinct characteristics. The exfoliation mechanisms of these three acids are illustrated in Figure 1. The synergistic combination of these acids offers a more comprehensive solution to keratinization issues.

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Figure 1:

Diagram of the exfoliation mechanism of three acids. NMF: Natural moisturizing factor, ATP: Adenosine triphosphate, DNA: Deoxyribonucleic acid, PKP: Plakophilin, PG: Plakoglobin, DP: Desmoplakin.

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Synergistic effects on sebum regulation

SA, AZA, and LA not only have significant effects on keratin regulation but also play important roles in sebaceous secretion control. SA, a lipophilic acid, due to its lipotropism, easily penetrates the sebaceous glands and antagonizes hyperseborrhea. A study by Lu et al. demonstrated that SA exhibited sebosuppressive properties primarily through the downregulation of the AMPK/SREBP-1 signaling pathway.²⁶ In addition, research by Zhang et al. further confirmed that SA could downregulate the expression of SREBP-1 and its downstream target enzymes Fatty acid synthase (FAS) and cyclooxygenase-2 (COX-2), thereby reducing sebum secretion in acne patients.²⁷ AZA, as a competitive inhibitor of mitochondrial oxidoreductases and 5α-reductase, can inhibit the conversion of testosterone to dihydrotestosterone, thereby exerting anti-androgenic and sebostatic effects.²⁸ Several studies have shown that AZA effectively suppresses sebum secretion by regulating sebaceous glands over the long term.^29,30

LA, an AHA, has good keratolytic properties and can help unclog skin pores, thereby enhancing the penetration and efficacy of SA and AZA. Moreover, a study by Chilicka et al. indicated that the combination of plant extracts, LA, and ultrasound had a positive impact on the skin of patients with acne vulgaris, reducing skin surface eruptions and sebum levels.³¹

Overall, the combined action of SA, AZA, and LA can effectively regulate skin sebum secretion and improve pore congestion, providing a better solution for the comprehensive management of acne. The mechanism of synergistic regulation of sebum by the three acids is illustrated in Figure 2.

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Figure 2:

Mechanism diagram of the synergistic regulation of sebum of three acids. mTORC1: Mammalian target of rapamycin complex 1, AMPK: AMP-activated protein kinase, SREBP-1: Sterol regulatory element-binding protein 1, DHT: Dihydrotestosterone.

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Acne-induced post-inflammatory erythema (PIE) and post-inflammatory hyperpigmentation (PIH)

AZA exerts a potent inhibitory effect on tyrosinase activity, thereby blocking the conversion of tyrosine to Dopamine (DOPA) and its subsequent product, DOPA-quinone, ultimately reducing melanin synthesis. In addition, AZA inhibits mitochondrial metabolism, DNA synthesis, and protein synthesis in melanocytes without affecting melanocytes in normal skin. Consequently, AZA can be safely used to treat various hyperpigmentary disorders without causing pigmentation changes in the surrounding healthy skin.³²

Moreover, AZA reduces the expression of serine protease kallikrein 5 and antimicrobial peptides, thereby decreasing the release of pro-inflammatory cytokines. By inhibiting the expression of interleukin (IL)-1, IL-6, and tumor necrosis factor-α, AZA also reduces reactive oxygen species and pro-inflammatory mediators.^33-35 These anti-inflammatory and anti-pigmentary effects enable AZA to significantly improve PIE and PIH induced by acne.

SA reduces acne-associated hyperpigmentation through its anti-inflammatory properties. In addition, studies have shown that SA can lower melanin levels and tyrosinase activity in normal epidermal melanocytes, inhibiting melanin synthesis and melanosome transport. This mechanism contributes to the reduction of pigmentation and alleviation of PIE and PIH.³⁶ SA has been demonstrated to be effective in treating post-acne hyperpigmentation.³⁷

LA facilitates epidermal desquamation, promoting keratinocyte turnover, improving skin texture, and enhancing skin brightness.³⁸ In addition, LA has been shown to directly inhibit tyrosinase activity in a dose-dependent manner, independent of its acidity, thereby reducing pigmentation and preventing PIH-related hyperpigmentation. Clinical and histological evidence suggests that topical application of LA effectively removes hyperpigmentation and improves skin roughness and fine wrinkles caused by environmental photodamage.^39,40

Collectively, AZA, SA, and LA exhibit well-defined efficacy in reducing post-acne inflammatory erythema and hyperpigmentation. Their synergistic mechanism in regulating acne-induced PIE and PIH is illustrated in Figure 3. The multi-target actions of these acids provide a scientifically validated approach to improving PIE and PIH.

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Figure 3:

Mechanism diagram of the synergistic regulation of acne-induced post-inflammatory erythema and post-inflammatory hyperpigmentation by three acids. IL: Interleukin, TNF: Tumor necrosis factor.

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Insights from existing acid combinations

The combination of AHAs and BHAs has garnered increasing attention in acne therapy due to their synergistic potential and complementary mechanisms of action. Extensive clinical studies and dermatological applications have demonstrated that multi-acid formulations can enhance therapeutic efficacy while mitigating the irritation commonly associated with monotherapy. These findings provide a solid rationale for exploring more complex combinations, such as triple-acid regimens.

One of the classic examples is Jessner’s solution, developed by dermatologist Max Jessner in the early 20^th century. This formulation combines SA, LA, and resorcinol (or citric acid) and has demonstrated clinical efficacy in treating acne, acne-related scarring, photoaging, and hyperpigmentation. Jessner’s solution remains widely used in superficial chemical peels and is considered both safe and effective across various skin types.⁴¹

Recent studies have further validated the benefits of acid combinations. For instance, Fanning et al. reported that a superficial peel containing 6% trichloroacetic acid (TCA) and 12% LA effectively reduced photoaging symptoms with minimal side effects compared to higher-strength TCA monotherapy.⁴² Similarly, Chauhan and Singh demonstrated that a combination of LA and ferulic acid significantly outperformed ferulic acid alone in reducing fine lines, pigmentation irregularities, and photodamage, emphasizing the enhanced bioactivity of synergistic acid blends.⁴³

Beyond AHA–BHA combinations, emerging evidence supports the therapeutic value of dual-acid regimens involving SA, AZA, and LA:

• SA + AZA: Abdel Hay et al. demonstrated that the combination of SA and AZA significantly improves inflammatory acne and provides better comfort compared to TCA.⁴⁴

• SA + LA: In a separate study, Mapar et al. showed that the combination of SA and LA effectively treated plantar and common warts without notable adverse effects.⁴⁵

Collectively, these findings suggest that dual-acid formulations offer superior clinical outcomes over monotherapy by enabling the use of lower concentrations of individual acids, thereby reducing cumulative irritation while maintaining efficacy. Such regimens have shown particular promise in individuals with Fitzpatrick skin types III and IV, where tolerability and PIH risk are of heightened concern.⁴⁶

These insights provide a strong theoretical and empirical foundation for the development of triple-acid combinations involving SA, AZA, and LA. Their complementary mechanisms offer a comprehensive, multi-targeted approach to acne management, laying the groundwork for next-generation, multi-functional skincare solutions with enhanced efficacy and safety.

Theoretical advantages of three acids combination in acne care

LA facilitates the removal of dead surface keratinocytes, promotes cell renewal, and reduces acne scarring. In addition, LA has moisturizing properties, enhances ceramide synthesis, provides cellular energy, and improves skin permeability. In contrast, BHA (such as SA) is lipophilic, allowing it to penetrate hair follicles, remove excess sebum, unclog pores, and exert anti-inflammatory effects by modulating the arachidonic acid pathway. Meanwhile, AZA inhibits tyrosinase activity to improve pigmentation while exhibiting strong antimicrobial properties that effectively reduce acne scars.

The combination of these three acids enables a comprehensive approach to acne management, targeting exfoliation, inflammation reduction, oil control, pigmentation inhibition, and skin repair. Their distinct mechanisms of action allow for the use of lower individual acid concentrations, thereby minimizing irritation. A well-formulated triple acid combination holds significant therapeutic potential in acne treatment.⁴⁷

In clinical practice, triple acid therapy offers remarkable efficacy and allows for personalized adjustments. For oily skin, higher concentrations of SA and AZA may be used to control sebum production and inflammation better. In contrast, for dry or sensitive skin, lower concentrations of SA and AZA with increased LA content can enhance hydration and skin repair. For patients with prominent acne scars, emphasizing the combination of AZA and LA can effectively improve pigmentation and promote scar healing.

By leveraging complementary mechanisms, the triple acid combination not only provides a more comprehensive treatment strategy but also significantly reduces acne marks and scars, further enhancing treatment outcomes. For patients who do not respond well to monotherapy or experience significant irritation, combination therapy may offer superior efficacy. Clinicians can tailor the concentrations of SA, AZA, and LA based on individual skin conditions to achieve personalized treatment.

Safety and tolerability

The safety profiles of SA, AZA, and LA as individual therapies are well-established. However, the safety and tolerability of their combined use in clinical settings remain insufficiently studied. SA’s keratolytic action may cause transient skin peeling, erythema, or dryness. AZA is generally well tolerated, but high concentrations may still trigger localized irritation. LA provides moisturizing benefits, but improper pH control may result in skin sensitivity or barrier impairment.

While the combination of these three acids could offer synergistic therapeutic benefits, it also raises concerns regarding the risk of skin irritation, especially in individuals with sensitive or darker skin types, where PIH is more prevalent. Therefore, rigorous clinical studies are required to assess both the short-term and long-term safety, tolerability, and applicability of triple acid formulations across diverse skin types.

Future research directions

To further advance the clinical application of triple acid therapy, future research should focus on the following aspects:

• Clinical validation: Conduct randomized controlled trials to evaluate the safety and efficacy of different concentrations and formulations of triple acid combinations, identifying optimal dosages and potential adverse effects.

• Personalized treatment approaches: Investigate factors such as skin barrier integrity, sebum secretion levels, and acne subtypes to enable more personalized treatment strategies tailored to individual skin profiles.

• Formulation optimization: Explore advanced delivery systems, such as microencapsulation, sustained-release formulations, microemulsions, and liposomes, to enhance formulation stability and minimize irritation.

• Combination therapies: Assess potential synergies between triple acid combinations and other anti-acne ingredients (e.g., niacinamide, retinoids, azeloyl glycine, antimicrobial peptides) to improve overall treatment outcomes.

Although initial findings are promising, clinical evidence remains limited. Future research should aim to establish a robust body of evidence to support the safe and effective use of triple acid therapy in clinical dermatology.