On January 21, the research teams led by Professor Sun Jinpeng and Professor Yu Xiao from Shandong University published two landmark studies on olfactory receptors back-to-back in Cell. Titled “Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target” and “Mechanistic Insights into Fatty Acid Odor Detection Mediated by Class II Olfactory Receptors” respectively, the two papers systematically elucidated the dual core functions of the Class II olfactory receptor Or5v1/Olfr110 in olfactory recognition and metabolic regulation: it can not only recognize PL45, a natural fatty acid odorant derived from the herbal plant Eupatorium fortunei, to mediate olfactory perception, but also respond to 12(S)-HEPE, an endogenous oxylipin, to regulate metabolic homeostasis. The research not only expands the boundaries of understanding olfactory receptor ligand recognition and functional diversity, but also achieves a groundbreaking breakthrough for olfactory receptor evolutionary studies, as well as the treatment and drug development of metabolic diseases. Shandong University is the first author and corresponding author institution for both studies.

G protein-coupled receptors (GPCRs) serve as direct therapeutic targets for approximately one-third of marketed drugs. However, nearly all existing drugs target non-olfactory GPCRs, and no clinical drugs have yet been developed for olfactory receptors—these receptors account for half of the GPCR superfamily. In humans, there are more than 300 olfactory receptors, which have long been thought to only recognize volatile odorants in the environment with low affinity, with their functions limited to mediating olfactory perception. Although previous studies have indicated that ectopically expressed olfactory receptors can regulate metabolic homeostasis, their potential as drug targets has lacked validation through rationally designed specific small molecules.

The first study, “Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target”, was led by the teams of Professor Sun Jinpeng and Professor Yu Xiao from Shandong University, in collaboration with Professor Yang Jichun from Peking University, Professor Chai Renjie from Southeast University, and Professor Hao Yong from Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. Professors Sun Jinpeng, Yang Jichun, Yu Xiao, Chai Renjie and Hao Yong are the co-corresponding authors. The co-first authors include Dr. Ge Xiaoyan (Postdoctoral Fellow), Professor Cheng Jie, Dr. Zhang Lijun (PhD Candidate), Professor Guo Lulu from the Advanced Medical Research Institute, Shandong University; Dr. Xiang Rui (Postdoctoral Fellow) from the School of Basic Medical Sciences, Peking University; Dr. Lu Yan (Postdoctoral Fellow), Dr. Ning Shanglei, Dr. Wang Kaiyu (PhD Candidate) from Shandong University.

Using the self-developed "ARIG" technology, the research identified the olfactory receptor Or5v1/Olfr110 (human ortholog OR5V1) as a high-affinity receptor for the oxylipin 12(S)-HEPE. Unlike traditional olfactory receptors that recognize environmental odorants with low affinity, 12(S)-HEPE—an endogenous ligand—activates Or5v1/Olfr110 at the nanomolar level. Analysis of clinical cohorts revealed a negative correlation between 12(S)-HEPE levels and clinical BMI indices. Mechanistically, 12(S)-HEPE promotes hepatic fatty acid oxidation through the Olfr110-Gs-PKA-pATF2-Cpt1α signaling pathway, thereby improving glycemic homeostasis and alleviating obesity. HOR1-C59, a small-molecule agonist developed to target this receptor, exerts Olfr110-dependent metabolic improvement effects.

The second study, “Mechanistic Insights into Fatty Acid Odor Detection Mediated by Class II Olfactory Receptors”, was conducted by the teams of Professor Sun Jinpeng, Professor Yu Xiao and Professor Yang Fan from Shandong University, in conjunction with Researcher Li Qian from Shanghai Jiao Tong University School of Medicine and Professor Xia Ming from Shandong First Medical University. Professors Sun Jinpeng, Yang Fan, Yu Xiao, Researcher Li Qian and Professor Xia Ming are the co-corresponding authors. The co-first authors include Dr. Han Xiang (PhD Candidate), Dr. Zhang Minghui (PhD Candidate), Dr. Rong Naikang (PhD Candidate) from the School of Basic Medical Sciences, Shandong University; Associate Researcher Zhu Kongkai, Dr. Ge Xiaoyan (Postdoctoral Fellow) from the Advanced Institute of Medical Sciences, Shandong University; and Assistant Researcher Pei Yuan from ShanghaiTech University.

The study screened and identified PL45, a natural unsaturated fatty acid from Eupatorium fortunei, as an effective activator of mouse Olfr110. Using cryo-electron microscopy (cryo-EM), the research resolved the structure of the PL45-Olfr110-Gs complex, and discovered that Olfr110 harbors a unique ultra-large ligand-binding pocket. Further studies confirmed that other members of the OR5 family within Class II olfactory receptors (e.g., OR5M9, OR5H6, OR5R1) can also be activated by unsaturated fatty acids, employing a dual-pocket architecture consisting of a "small polar pocket + large hydrophobic pocket" that recognizes the polar head and hydrophobic fatty chain of ligands, respectively. This study is the first to uncover the structural mechanism underlying the recognition of hydrophobic odorants by Class II olfactory receptors, providing critical theoretical basis for understanding the functional adaptation of olfactory receptors during the evolution of vertebrates from aquatic to terrestrial habitats.

Collectively, this series of studies systematically demonstrated that the olfactory receptor Or5v1/Olfr110 can both recognize PL45 (a natural fatty acid odorant from Eupatorium fortunei) in the nasal cavity to mediate olfactory perception, and respond to 12(S)-HEPE (an endogenous oxylipin ligand) to regulate metabolic homeostasis. Small-molecule compounds targeting this receptor exhibit therapeutic effects on obesity, which not only validates the feasibility of olfactory receptors as drug targets, but also opens up a novel avenue for the treatment of metabolic diseases such as obesity, diabetes and fatty liver disease.

Professor Yu Xiao's previous work identified that OLFR109, an ectopically expressed olfactory receptor in pancreatic islets, can recognize misfolded insulin or insulin short peptides, and impairs islet homeostasis and exacerbates diabetes progression by reprogramming islet-resident macrophages. This work was published in Cell Metabolism(Cell Metab. 2022 Feb 1;34(2):240-255.e10) with Professor Yu as the senior corresponding author. The two Cell papers represent a continuation of this research, and are part of Professor Yu's long-term series of studies on ectopically expressed olfactory receptors in metabolism.

Professor Sun Jinpeng's team has long been dedicated to research on GPCR microenvironment pharmacology and sensory pharmacology, focusing on GPCR ligand discovery, drug target validation, functional studies, and peptide/small-molecule drug design. The team has achieved a series of original research outcomes, including the discovery of the steroid membrane receptor subfamily, ceramide membrane receptors, and GPCRs mediating hearing and balance. Professor Sun has published more than 130 papers as a corresponding author in top-tier journals including Nature(9 papers), Science(2 papers), Cell(8 papers), Cell Metabolism(2 papers), and Nature Metabolism(2 papers).