Gpr35 Links Linoleic Acid Breakdown to Psoriasis-Like Itch

A single bloodstream dose of a Gpr35-blocking drug reduced EKODE-driven scratching in mice, including a psoriasis-like skin model, in a Communications Biology study published online October 29, 2026.

First author Joshua J. Wheeler, corresponding author Santosh K. Mishra of North Carolina State University College of Veterinary Medicine, and colleagues published “Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits” in Communications Biology, volume 9, article 1393. They combined cultured cells, mouse sensory nerves, genetically modified mice, and mouse models of psoriasis-like inflammation and atopic dermatitis.

The candidate trigger was EKODE, a breakdown product of linoleic acid, the most abundant omega-6 fat in skin and modern diets and a component of cooking oils and packaged foods. Earlier work cited by the authors found much higher EKODE levels in psoriasis lesions than in unaffected skin from the same patients.

Earlier animal studies linked high-linoleic-acid diets with inflammatory skin compounds and greater pain sensitivity. People with obesity who eat industrialized diets are more likely to develop psoriasis, although that association does not establish cause.

In laboratory tests, about 9% of mouse sensory nerve cells near the spinal cord produced a calcium surge after EKODE exposure. They also reacted to histamine and other itch or pain triggers. Chemical blockers implicated a cell-surface receptor family, then narrowed the search to Gpr35.

In cultured human kidney cells, only those carrying Gpr35 and a partner protein that helps sensory neurons detect itch and pain responded to EKODE; neither alone sufficed. Mouse nerve cells engineered to lack Gpr35 also responded less.

In living mice, deleting Gpr35 from a large population of pain- and itch-sensing nerve cells reduced EKODE-induced scratching. Groups were small, often 6 to 8 mice. Histamine scratching remained normal in both groups, suggesting a specific role in the EKODE route rather than all itch.

A single bloodstream dose of a Gpr35 blocker produced a similar reduction. It also eased scratching in mouse models of psoriasis-like inflammation, induced with an irritating cream, and atopic dermatitis. Cream-treated skin contained measurable EKODE; Vaseline-treated skin contained none.

Gpr35 sits alongside the itch messenger Nppb on sensory neurons. Roughly half of Gpr35-bearing mouse neurons also carried Nppb, and Nppb-deficient mice scratched less after EKODE and in the psoriasis-like model. The authors propose that EKODE activates Gpr35, releases Nppb, and sends the signal toward the spinal cord.

Mice without Gpr35 also took longer to withdraw from very hot surfaces, including a plate heated to about 131°F. Responses to moderate heat, pressure, and cold did not change, hinting at a role in intense heat pain.

What does this change for clinicians?

The practical answer is a neural target, not a diet prescription. In the psoriasis-like model, Gpr35-deficient mice scratched less and had thinner skin, yet showed higher levels of two inflammation signals associated with psoriasis. That dissociation suggests itch and inflammation can run on partly separate tracks, which may explain persistent itching despite anti-inflammatory treatment.

It does not show that blocking Gpr35 will control human psoriasis itch, or that reducing linoleic acid will help. Human evidence remains circumstantial: genetic data showed active Gpr35 in human sensory nerve tissue, overlapping Nppb-making cells. Staining of tissue from two human samples found Gpr35 in every Nppb-making cell.

Researchers have not tested whether EKODE activates the human receptor. An earlier large human genetic study linked Gpr35 variants with psoriasis risk, and the authors suggest receptor differences could make some people more susceptible to chronic itch and inflammation.

Human findings show presence, not causation.

Where the evidence stops

• Most experiments used mice or cultured cells; groups were small, and human staining involved two samples. The cream-induced psoriasis model does not fully reproduce human disease.
• The source of elevated EKODE remains unknown. The authors suspect keratinocytes or immune cells entering the affected area.
• Trpv1 results diverged: deleting it did not block isolated-cell calcium responses, yet reduced itching in living mice. They suggest it amplifies the signal rather than detecting EKODE directly.
• Diet was not tested. Human diet studies remain difficult, with animal studies proposed next; the active human Gpr35 variants and their response to EKODE also remain unknown.

Study record and competing interests

North Carolina State startup funds supported Mishra, with support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and private gifts; one author received an institutional training grant. Christopher E. Ramsden and Gregory S. Keyes were supported by the National Institute on Aging’s Intramural Program.

Mishra filed a North Carolina State invention disclosure, “Therapeutic Potential of GPR35 Blockers in inflammation and itch,” with Brian S. Kim as co-inventor; the paper states that an IP filing is not applicable.

Kim co-founded Alys Pharmaceuticals and Neurommune Therapeutics, consults for pharmaceutical and biotechnology companies, holds stock in several, and holds a patent on JAK1 inhibitors for chronic itch. Remaining authors declared no competing interests.

Additional authors were Alla Lyfenko, Nesia A. Zurek, Keaton Song, Andy Wangzhou, Sruti Bontala, Ojasvi Deep, Jacob Casey, Ramsey Kubofcik, Daniel L. Schaffer, Hassan Melhem, Gregory S. Keyes, John M. Davis, Jan Hendrik Niess, Theodore J. Price, Christopher E. Ramsden, Brian S. Kim, and Sascha R. A. Alles. Affiliations included North Carolina State University, Cincinnati Children’s Hospital Medical Center, Icahn School of Medicine at Mount Sinai, University of Texas at Dallas, University of Basel, University of Illinois at Chicago, Northwell Health, and the National Institutes of Health.

The open-access paper was received February 10, 2026, accepted September 21, 2026, and published online October 29, 2026 under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 license. DOI: https://doi.org/10.1038/s42003-026-11087-x.

The result gives dermatology a defined pathway to test in human tissue and trials. A research lead, not kitchen advice.