The aryl hydrocarbon receptor: Tapinarof is taking off

By Warren R. Heymann, MD, FAAD
Nov. 19, 2025
Vol. 7, No. 46

In his outstanding lecture identifying drivers of lupus, presented at the 2025 meeting of the Medical Dermatology Society, Jaehyuk Choi MD, PhD, explained that interferon — the well-known nemesis of lupus — controls the production of T cells that promote lupus. In an interesting seesaw, interferon promotes B-helper T cells and inhibits Th22 cells from producing interleukin-22 (IL-22). Inhibition of interferon with anifrolumab significantly reduces the levels of circulating B-helper T cells and increases the number of Th22 cells in the blood of lupus patients. Conversely, he explained that on the other side of the seesaw, the aryl hydrocarbon receptor (AHR) promotes Th22, which could help rebalance the lupus pathophysiology axis. (1)

I had the pleasure of sitting between Caroline Nelson from Yale and Brian Chu, a Brown dermatology resident; I turned to them and said, if the AHR receptor does this, then theoretically, tapinarof should be beneficial in lupus. We quickly searched PubMed and found a case report of nasal discoid lupus responding to tapinarof 1% cream in a 56-year-old woman, which was previously unresponsive to clobetasol and tacrolimus. (2)

Tapinarof (Vtama) is FDA-approved for psoriasis and atopic dermatitis (AD). Three years ago, I wrote a commentary about tapinarof discussing its potential use in AD. (3) In 2019, I was excited to learn about the AHR and how tapinarof could help treat psoriasis in a far more elegant way than crude coal tar (CCT). In my commentary from “A Clinician’s Perspective” in the JAAD (4), I wrote:

Recent studies have elucidated the mysteries of coal tar’s benefit. Through use of organotypic skin models with primary keratinocytes from patients with AD and controls, it has been demonstrated that coal tar activates the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation, restoration of filaggrin expression, and counteraction of type 2 helper T cell cytokine–mediated downregulation of skin barrier proteins. Coal tar interferes with type 2 helper T cell cytokine signaling via dephosphorylation of signal transducer and activator of transcription 6, most likely as a result of AHR-regulated activation of the nuclear factor, erythroid 2 like antioxidative stress pathway. These findings suggested that the therapeutic effect of AHR activation could lead to the development of new mechanism-based drugs for AD.

Tapinarof is a bacteria-derived polyphenol that acts on the AHR and nuclear factor erythroid 2–related factor 2 (a basic leucine zipper protein) that protect against inflammatory-induced oxidative damage. Tapinarof also has free radical scavenging ability. In a study using a mouse model of imiquimod-induced psoriasiform skin lesions, topical treatment of AHR-sufficient mice with tapinarof led to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. Tapinarof had no impact on imiquimod-induced skin inflammation in AHR-deficient mice. This study clearly demonstrated that the anti-inflammatory properties of tapinarof are due to AHR agonism.

(I have no conflict of interest regarding tapinarof — financial or otherwise.)

AHR is expressed in keratinocytes, melanocytes, fibroblasts, and resident immune cells, including Langerhans cells and γδ T cells. AHR is highly expressed in keratinocytes, where it is involved in keratinocyte differentiation and skin barrier formation. Dawe and DiMeglio expertly outline the AHR pathway: AHR is held in an inactive state in the cytoplasm by chaperone proteins HSP [heart shock protein] 90, AIP [AHR-interacting protein], p23, and protein kinase SRC, preventing its degradation, and keeping it in a high-affinity conformation for ligands. Once bound by a ligand, AHR and its chaperone complex can translocate into the nucleus, where the ARNT [AHR Nuclear Translocator] can bind to AHR, causing its dissociation from the complex. The AHR/ARNT dimer can then bind to regions of DNA that possess the XRE [xenobiotic response element], initiating transcription of AHR’s target genes AHRR [AHR repressor], CYP1 [cytochrome P450 1]A1, CYP1A2, CYP1B1, and TIPARP [TCDD-inducible poly(ADP-ribose) polymerase. Following activation, AHR is highly regulated at three levels to prevent overactivation of the pathway. (5)

AHR is a crucial regulator in the pathogenesis of autoimmune disorders. T follicular helper (Tfh) and T peripheral helper (Tph) cells are populations of helper T-cells essential for the biological progression of plasma cell development, formation of germinal centers and antibody production, and thus necessary for the development of autoantibody driven autoimmune diseases, such as lupus. Law et al. showed that AHR agonists can diminish the levels of these cells from the blood of patients with lupus (1). Zhang et al. demonstrated that intraperitoneal administration of tapinarof in mice ameliorated lupus phenotypes, including splenomegaly, lymph node enlargement, kidney damage, immune complex deposition, and excessive secretion of antibodies. Mechanistically, tapinarof significantly inhibited the phosphorylation levels of JAK2 and STAT3. (6)

Regarding off-label use of tapinarof, the agent improved a palmoplantar keratoderma in an ichthyotic patient (whose whole exome sequencing did not reveal the genetic variation), possibly by downregulating IL-17. (7) According to Bitterman et al. in their review of AHR agonists in treating vitiligo, “culturing AhR agonists with melanocytes upregulates melanin-synthesizing enzymes, reduces reactive oxygen species, and modulates pro-inflammatory cytokines such as IL-17A and IL-22. Tapinarof, a topical AhR agonist used commonly for the treatment of psoriasis, demonstrated clinical efficacy in repigmentation with a favorable safety profile compared to long-term steroid use.” (8) Greene et al. reported the clearance of perioral dermatitis with tapinarof in a 63-year-old woman. (9)

Crude coal tar (CCT) has been used therapeutically for at least 2000 years for skin disease. The precise composition of CCT produced at one time is distinct from other batches. CCT is roughly composed of 10,000 compounds consisting of approximately 48% hydrocarbons, 42% carbon and 10% water. In their 2002 review of coal tar, Thami and Sarkar predicted that use of CCT in skin diseases would likely become increasingly limited over time, probably confined to a few psoriasis patients with good compliance in developing countries. Strict regulations regarding its preparation, controversial carcinogenic potential, and health and safety concerns would curtail CCT use. While their prediction had credence, what they did not foresee was the comprehension of AHR pathophysiology that would allow for the development of refined therapies such as tapinarof. The therapeutic potential of this agent seems limitless.

Point to Remember: The aryl hydrocarbon receptor plays a key role in inflammation. Understanding its pathophysiology has led to new therapeutic agents such as tapinarof, which is approved for psoriasis and atopic dermatitis, and used off-label in lupus, vitiligo, ichthyotic diseases, and perioral dermatitis.

Our expert’s viewpoint

Jaehyuk Choi, MD, PhD, FAAD
Director, Center for Cellular Therapies and Cancer Immunology, Harold C. Simmons Comprehensive Cancer Center
Vice Chair for Translational Research and Innovation, Department of Dermatology
UT Southwestern

We have discovered a hidden logic that controls pathogenic inflammation in lupus. Surprisingly, a chemical imbalance in patients’ blood appears to control the production of the disease-promoting immune cells in lupus, i.e. the B helper T cells. The chemical imbalances occur through a cascade of type I interferon and of aryl hydrocarbon receptor. Interestingly, this pathway can be targeted at multiple levels including with interferon blockade, such as with anifrolumab, and with aryl hydrocarbon receptor agonists. To test this concept, Dr. Paras Vakharia of Northwestern Dermatology is starting a clinical trial to test the effects of taparinof on cutaneous lupus (NCT06661213). If successful, this may represent a novel therapy whereby the disease-causing immune cells are not blocked or eliminated but instead reprogrammed.

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References

1. Law C, Wacleche VS, Cao Y, Pillai A, Sowerby J, Hancock B, Horisberger A, Bracero S, Skidanova V, Li Z, Adejoorin I, Dillon E, Benque IJ, Nunez DP, Simmons DP, Keegan J, Chen L, Baker T, Brohawn PZ, Al-Mossawi H, Hao LY, Jones B, Rao N, Qu Y, Alves SE; Accelerating Medicines Partnership: RA/SLE Network; Jonsson AH, Shaw KS, Vleugels RA, Massarotti E, Costenbader KH, Brenner MB, Lederer JA, Hultquist JF, Choi J, Rao DA. Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus. Nature. 2024 Jul;631(8022):857-866. doi: 10.1038/s41586-024-07627-2. Epub 2024 Jul 10. Erratum in: Nature. 2024 Aug;632(8025):E6. doi: 10.1038/s41586-024-07845-8. PMID: 38987586; PMCID: PMC11628166.

2. Garg KS, Tjahjono L. Successful treatment of discoid lupus erythematosus with tapinarof 1% cream monotherapy. JAAD Case Rep. 2024 Sep 30;54:1-2. doi: 10.1016/j.jdcr.2024.09.010. PMID: 39552756; PMCID: PMC11566309.

3. Heymann WR. Tarrying for tapinarof. Dermatology World Insights and Inquiries. January 12, 2022, Vol.4, No. 2 https://staging.aad.org/dw/dw-insights-and-inquiries/archive/2022/tarrying-for-tapinarof

4. Heymann WR. "Tar smarts" may have a new meaning for atopic dermatitis and psoriasis. J Am Acad Dermatol. 2019 Jan;80(1):56-57. doi: 10.1016/j.jaad.2018.10.057. Epub 2018 Nov 3. PMID: 30395913.

5. Dawe HR, Di Meglio P. The Aryl Hydrocarbon Receptor (AHR): Peacekeeper of the Skin. Int J Mol Sci. 2025 Feb 14;26(4):1618. doi: 10.3390/ijms26041618. PMID: 40004095; PMCID: PMC11855870.

6. Zhang Y, Pan Y, Zhang P, Wang F, Han Y, Li K, Jiang W, Wang J, Luan Y, Xin Q. AhR agonist tapinarof ameliorates lupus autoimmunity by suppressing Tfh cell differentiation via regulation of the JAK2-STAT3 signaling pathway. Immun Inflamm Dis. 2023 Jun;11(6):e903. doi: 10.1002/iid3.903. PMID: 37382269; PMCID: PMC10266146.

7. Robinson SN, Kranseler JS, Rosmarin D. Treatment of palmoplantar keratoderma in a patient with ichthyosis with topical tapinarof. JAAD Case Rep. 2024 Jan 27;45:66-67. doi: 10.1016/j.jdcr.2024.01.017. PMID: 38389856; PMCID: PMC10882012.

8. Bitterman D, Kabakova M, Wang JY, Collins A, Patel P, Gupta N, Zafar K, Cohen M, Jagdeo J. The role of aryl hydrocarbon receptor agonists in the treatment of vitiligo. Arch Dermatol Res. 2024 Oct 5;316(9):659. doi: 10.1007/s00403-024-03405-2. PMID: 39369105.

9. Greene A, Hamann CR, McBride M. Clearance of Periorificial Dermatitis with Tapinarof. Dermatitis. 2024 Sep 23. doi: 10.1089/derm.2024.0277. Epub ahead of print. PMID: 39311695.

10. Thami G, Sarkar R. Coal tar: past, present and future. Clin Exp Dermatol. 2002 Mar;27(2):99-103. doi: 10.1046/j.1365-2230.2002.00995.x. PMID: 11952698.

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