A team of researchers has found that a breakdown product from a commonly consumed fat can bind to a receptor associated with psoriatic itch and inflammation. By blocking the receptor, the researchers saw a reduction in psoriatic itch in a mouse model. The work demonstrates the potential impact of diet on chronic itch triggers and could lead to future therapies for both psoriasis and atopic dermatitis.
Linoleic acid is a naturally occurring fatty acid that is found in foods ranging from nuts and seeds to vegetable oils. While humans need to consume linoleic acid in small amounts, overconsumption has been associated with chronic heart disease and diabetes, among other conditions.
“We also know that certain polyunsaturated fat-derived molecules are associated with itch, and that linoleic acid is the most abundant polyunsaturated fat found in both skin and western diets,” says Santosh Mishra, professor of molecular and biomedical sciences in North Carolina State University’s College of Veterinary Medicine. “We wanted to explore connections between linoleic acid and itch.” Mishra is the corresponding author of the study describing the work.
Specifically, the researchers focused on a derivative of linoleic acid known as 9-keto-12,13-epoxy octadecenoic acid (EKODE), which has been found in high concentrations in psoriatic lesions and shown to induce itching behavior in mice.
In humans and rodents, primary sensory neurons within the dorsal root ganglia (DRG) express specific ion channels, including TRPV1 and TRPA1, which mediate pain, thermal sensation, and itch.
Using EKODE, mouse DRG and cultured human DRG neurons, the researchers found the signaling pathway that connected EKODE from periphery in the skin to the spinal cord via a neuropeptide called BNP, which is specifically associated with itch response.
In short, they found that EKODE binds to and activates a receptor called GPR35 on sensory neurons, which in turn release BNP and drive the itch response.
The researchers also confirmed GPR35 receptor expression on “TRPV1” and “TRPA1” sensory neurons in both rodent and human DRG neurons.
Next, the researchers looked at how the pathway works in a mouse model of psoriasis. They compared itch response to EKODE in mice with and without the GPR35 receptor and found that the GPR35 knockout mice had less inflammation and itch than those with GPR35.
They did the same thing with BNP knockout mice and saw similarly reduced itch and inflammation in the psoriasis model.
Finally, they treated a mouse model of eczema with a GPR35 blocker and found that the itch response was significantly reduced in that case as well.
The researchers hope that the work can lead to therapies for both psoriasis and other chronic itch conditions, like atopic dermatitis, in both human and veterinary fields.
“The work shows the importance of GPR35 because this receptor is connected to two totally different diseases – one autoimmune and one allergic,” Mishra says. “But in both diseases the itch pathway is using the same receptor, which means that GPR35 is a promising therapeutic target for both diseases.”
The work appears in Communications Biology . The National Institutes of Health provided approximately 50% of the support for the work. Joshua Wheeler, postdoctoral researcher at NC State, is the first author. Other NC State contributors include Alla Lyfenko, Sruti Bontala, Ojasvi Deep, and Jacob Casey. Nesia A. Zurek and Sascha R.A. Alles of Cincinnati Children’s Hospital Medical Center; Keaton Song, Ramsey Kubofcik, Daniel L. Schaffer and Brian S. Kim of the Icahn School of Medicine at Mount Sinai; Andy Wangzhou and Theodore Price of the University of Texas at Dallas; Hassan Melhem and Jan Hendrik Niess of the University of Basel, Switzerland; Gregory S. Keyes and Christopher E. Ramsden of the National Institutes of Health; and John M. Davis of the University of Illinois at Chicago also contributed to the work.
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Note to editors: An abstract follows.
“Metabolic Sensor Gpr35 Links Dietary Lipids to Itch-Mediating Neural Circuits”
DOI: 10.1038/s42003-026-11087-x
Authors: Joshua J. Wheeler, Alla Lyfenko, Sruti Bontala, Ojasvi Deep, Jacob Casey, Santosh Mishra, North Carolina State University; Nesia A. Zurek, Sascha R.A. Alles, Cincinnati Children’s Hospital Medical Center; Keaton Song, Ramsey Kubofcik, Daniel L. Schaffer, Brian S. Kim, Icahn School of Medicine at Mount Sinai; Andy Wangzhou, Theodore Price, University of Texas at Dallas; Hassan Melhem, Jan Hendrik Niess, University of Basel, Switzerland; Gregory S. Keyes, Christopher E. Ramsden, National Institutes of Health; John M. Davis, University of Illinois at Chicago
Published: Oct. 29, 2026 in Communications Biology
Abstract:
Impact of nutrition on systemic health is well-recognized but the specific sensors that couple western dietary lipid metabolites into the pathological triggers of chronic itch and inflammation remain elusive. Here, we identify a metabolic- to-sensory axis in which EKODE, an endogenous dietary linoleic acid derivative, acts as a potent ligand for the G protein-coupled receptor (Gpr35) to drive chronic itch, inflammation, and heat hypersensitivity. We demonstrate that Gpr35 is selectively expressed in a distinct population of sensory neurons and genetic ablation of Gpr35 in sensory neurons attenuates EKODE and psoriasis-associated itch and inflammation. Furthermore, pharmacological inhibition of Gpr35 significantly attenuates itch in mouse models of psoriasis and atopic dermatitis. We show that Gpr35 signaling engages the itch-specific neuropeptide BNP (or Nppb), defining a labeled-line pathway that is functionally distinct from classical nociceptive circuits. Collectively, our findings establish Gpr35 as a critical neuro-metabolic sensor in healthy and disease conditions.
Communications Biology
Experimental study
Animals
Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits
29-Oct-2026
S.K.M. filed an invention disclosure at Office of Technology Licensing at North Carolina State University. NCSU Ref #2026-023 titled “Therapeutic Potential of GPR35 Blockers in inflammation and itch”. Inventors: S.K.M. & B.S.K.; IP filing not applicable. All other authors declare no competing interests.