Why tretinoin is not used in cosmetics

Retinoids have long been considered the gold standard for correcting signs of photoaging: they accelerate epidermal turnover, reducing signs of keratosis and evening out skin tone [1, 2]. However, 9-cis retinoic acid, known as tretinoin, is classified as a pharmaceutical drug and is not used in cosmetic formulations. This is because tretinoin excessively activates retinoic acid receptor gamma (RARγ) in complex with retinoid X receptor (RXR), which overstimulates keratinocyte proliferation, increases expression of proinflammatory cytokines, and disrupts epidermal barrier integrity [3]. Clinically, this manifests as irritation, erythema, and heightened skin sensitivity, with this reaction occurring more frequently in individuals of Chinese descent than in other ethnic groups [4].

A further limitation of traditional retinoids is their effect on pigmentation: tretinoin can enhance melanocyte activation and proliferation and potentiate UV-induced hyperpigmentation, which is particularly undesirable when correcting photoaging [5].

This has driven researchers to search for retinoic acid derivatives that retain therapeutic efficacy while being safer and suitable for long-term topical use. One of the most promising such compounds is hydroxypinacolone 9-cis retinoate (9-cis HPR) [1].

What Is 9-cis HPR and how does it work

9-cis HPR is a synthetic ester analog of tretinoin. Unlike classic retinoids, which require metabolic conversion to bind receptors, the ester form allows the compound to penetrate the stratum corneum and directly interact with nuclear receptors in the skin.

The molecule's key feature is a bent spatial configuration characteristic of the 9-cis isomer, which enables selective dual activation of two receptors: RARα and RXRα. This fundamentally distinguishes 9-cis HPR from retinol and tretinoin, which predominantly and excessively activate RARγ/RXR.

Activation of RARα, which predominates in the dermis and dermal fibroblasts, enhances fibroblast function, extracellular matrix remodeling, and collagen synthesis.

Activation of RXRα, according to available data, has an anti-inflammatory effect, supports skin barrier function, and modulates RARα activity, preventing its excessive stimulation.

Thus, owing to its distinct receptor profile, 9-cis HPR may deliver efficacy comparable to tretinoin with substantially less irritant potential.

Study aim and design

This study aimed to investigate the potential of 9-cis HPR to correct signs of photoaging and its mechanisms of action—controlling inflammation, stimulating extracellular matrix regeneration, and suppressing melanogenesis—as well as to evaluate the compound's safety.

The study encompassed several levels of evidence.

In vitro. First, using HEK293T cells, the authors confirmed that 9-cis HPR selectively activates RARα and RXRα, while RNA sequencing of human dermal fibroblasts showed activation of the retinoic acid signaling pathway.

Animal models. Next, the compound's effects were studied in a photoaging model using SKH-1 hairless mice: after ten weeks of chronic UV irradiation, the animals received 0.03% or 0.1% 9-cis HPR for eight weeks. Using single-cell sequencing and spatial transcriptomics, the authors analyzed in detail how the compound affects different skin cell types.

Clinical study. The final stage was a single-masked, split-face clinical study involving 31 women, in which 0.03% 9-cis HPR was compared with 0.3% retinol over 28 days.

Results

• Extracellular matrix and skin cell balance

Single-cell analysis showed that irradiation disrupts the skin's cellular balance — decreasing the proportion of immune and basal cells while increasing the proportion of endothelial cells and melanocytes — and treatment with 9-cis HPR restored this balance and markedly increased the proportion of fibroblasts.

The compound also affected fibroblast subtypes differently depending on dose: the 0.03% concentration suppressed excessive differentiation into myofibroblasts (thereby reducing fibrosis risk) and enhanced an immunoregulatory subtype, while 0.1% more strongly restored the fibroblast subtype responsible for extracellular matrix remodeling. At the molecular level, 9-cis HPR increased expression of genes for collagen types I, III, IV, V, and VI, elastin, and fibronectin-1, which was confirmed by histological and immunohistochemical analysis.

In mice, 9-cis HPR significantly reduced UV-induced erythema, scaling, and wrinkling, restored collagen and elastin density, and improved skin elasticity.

• Pigmentation and inflammatory response

The effect on pigmentation deserves particular attention: 9-cis HPR suppressed expression of melanogenesis genes (Tyr, Dct, Tyrp1), melanosome formation genes (Mlana, Pmel), and the melanocyte proliferation gene Kit, and also weakened fibroblast–melanocyte crosstalk by reducing stem cell factor (SCF) production — as a result, both the proportion of melanocytes and the intensity of pigmentation marker staining decreased.

Notably, the compound also triggered a moderate, controlled activation of inflammatory signals (IL-6, CCL8, CXCL12) in fibroblasts—the authors interpret this not as pathological inflammation but as a necessary step in coordinating reparative processes that accompany tissue restoration.

• Human clinical trial results

In the human clinical trial, 0.03% 9-cis HPR over 28 days produced results comparable to or exceeding those of 0.3% retinol, despite the active ingredient concentration being ten times lower. Improvements were observed in wrinkles (particularly nasolabial folds), dermal density, stratum corneum hydration, elasticity, and skin radiance.

Notably, neither the human tests nor the animal irritation and phototoxicity tests showed any signs of skin irritation — the tolerability of 9-cis HPR was higher than that of retinol.

Study limitations

Limitations noted by the authors themselves include the need for expanded clinical trials involving more diverse populations in terms of age, ethnicity, and degree of photodamage, as well as detailed time-course studies to clarify the dynamics of the fibroblast inflammatory response and the role of individual signaling molecules.

Practical significance and cosmetic applications

For practicing specialists and cosmetic formulators, this study holds practical interest for several reasons:

• 9-cis HPR demonstrates a mechanism of action comparable to classic retinoids in its effects on the extracellular matrix and pigmentation, but with a substantially better tolerability profile, confirmed by both laboratory and clinical data;
• the compound combines selective activation of RARα and RXRα receptors, pronounced stimulation of collagen and elastin synthesis, balanced modulation of inflammation, and control of pigmentation, achieving an anti-photoaging effect without the irritation and hyperpigmentation risk characteristic of traditional retinoids;
• This makes the compound a promising candidate for inclusion in anti-aging cosmetic formulations, including those designed for sensitive skin or for consumers who have previously had difficulty tolerating classic retinoids.

Further studies in broader populations are certainly needed, but the data obtained so far position 9-cis HPR as a promising, safer alternative to traditional retinoids in anti-aging formulations.

References

1. Hu F., Yu J., Zheng C. et al. Hydroxypinacolone 9-cis retinoate mitigates UV-induced photoaging by modulating extracellular matrix, fibroblasts, inflammation, and melanogenesis. J Invest Dermatol 2026; 146(8): 2105–2127.
2. Zasada M., Budzisz E. Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments. Postepy Dermatol Alergol 2019; 36: 392–397.
3. Kim B.H., Lee Y.S., Kang K.S. The mechanism of retinol-induced irritation and its application to anti-irritant development. Toxicol Lett 2003; 146: 65–73.
4. Goh C.L., Tang M.B., Briantais P. et al. Adapalene gel 0.1% is better tolerated than tretinoin gel 0.025% among healthy volunteers of various ethnic origins. J Dermatol Treat 2009; 20: 282–288.
5. Welsh B.M., Mason R.S., Halliday G.M. Topical all-trans retinoic acid augments ultraviolet radiation-induced increases in activated melanocyte numbers in mice. J Invest Dermatol 1999; 112: 271–278.