Ferroptosis and Polyunsaturated Fatty Acid Metabolism

This research program investigates how dietary lipids and environmental chemicals interact at the molecular level to influence human health. The central focus of Dr. the Lee laboratory is the biological impact of the dietary balance between omega-3 and omega-6 polyunsaturated fatty acids - specifically, how the ratio of omega-3 (including DHA, EPA, and fish oil derivatives) to omega-6 (including arachidonic acid and soybean oil derivatives) contributes to disease processes and physiological regulation. this team's work is motivated by evidence that metabolites derived from these fatty acids are bioactive and may mediate many of the observed health effects associated with dietary lipid intake. A particular class of metabolites, fatty acid epoxides, emerges as a critical signaling hub: epoxides formed from omega-3 and omega-6 lipids influence inflammation, blood pressure regulation, organ protection, wound healing, cancer biology and pain perception.

Despite their importance, the mechanisms by which these epoxides initiate cellular signaling and exert diverse physiological effects have remained poorly defined. To address this gap, the lab team combines organic chemistry, chemical biology and state-of-the-art analytical instrumentation to design and synthesize chemical probes and molecular mimics of omega-3 and omega-6 fatty acid epoxides. These tailored mimics serve two interlocking purposes. First, they function as investigative tools to interrogate how fatty acid epoxides engage cellular receptors and downstream signaling pathways. Second, they provide scaffold structures that can be optimized for improved pharmacological properties, advancing the potential translation of basic findings into therapeutic candidates. Using selected mimics, the lab has progressed from probe design to functional discovery, including the identification of a receptor for a fatty acid epoxide.

This milestone exemplifies the lab's translational trajectory: mechanistic discovery guides molecular optimization, and optimized molecules feed back into deeper biological interrogation. Beyond receptor identification, the research program pursues structure-based refinement of mimics to enhance drug-likeness - for example, improving stability, selectivity, and bioavailability - with an eye toward developing candidate compounds that could modulate inflammation, vascular function, pain or cancer-related pathways.

By elucidating receptor interactions and optimizing epoxide mimics toward therapeutic profiles, the lab aspires to move discoveries from molecular mechanism to potential clinical application.