In Memoriam: David J. Mangelsdorf, Ph.D., pioneer in orphan nuclear receptor research and Chair of Pharmacology
DALLAS – Aug. 9, 2025 – David J. Mangelsdorf, Ph.D., Chair and Professor of Pharmacology at UT Southwestern Medical Center, a visionary scientist who pioneered the once-obscure realm of orphan nuclear receptors (a class of proteins involved in gene regulation) and uncovered key cellular signaling pathways, died Aug. 3 at the age of 67.
His discoveries over the course of 30 years at UT Southwestern were instrumental in advancing the understanding of diabetes, obesity, cancer, alcohol intoxication, and parasitic infections.
An Investigator of the Howard Hughes Medical Institute, Dr. Mangelsdorf was also elected to both the National Academy of Sciences (NAS) and the National Academy of Medicine (NAM) – rare and distinguished honors that reflect his prolific impact on basic science and clinical applications such as drug development and treatment strategies. His publications remain among the most cited in the field of molecular pharmacology.
“Dr. Mangelsdorf’s passing is an immense and painful loss for his family and friends, our institution, and the broader field of biomedical science,” said Daniel K. Podolsky, M.D., President of UT Southwestern. “His work exemplified the spirit of scientific innovation and collaboration at UT Southwestern, and his legacy will live on through the investigators he mentored and the lives improved by his discoveries.”
A cherished member of the UT Southwestern faculty, Dr. Mangelsdorf was best known as “Davo” to his colleagues. His friendly and curious nature fostered significant multidisciplinary studies spanning biochemistry, endocrinology, metabolism, neurology, and infectious diseases.
Since 2002, Dr. Mangelsdorf had run a joint laboratory with longtime scientific collaborator Steven Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology, and a fellow member of the NAS. Their early work identifying the ligands and physiological functions of orphan nuclear receptors led to the discovery of two novel signaling pathways mediated by the endocrine factors FGF19 and FGF21, which regulate nutrient metabolism during feeding and fasting. These discoveries revealed promising therapeutic targets for conditions such as cholestasis, Type 2 diabetes, and obesity. The Mangelsdorf/Kliewer Lab also uncovered a nuclear receptor pathway in parasitic nematodes and demonstrated that compounds targeting this pathway may represent a new class of antiparasitic agents.
“Davo was a wonderful scientific partner and friend. He was amazingly curious and creative, always pushing the scientific envelope. His enthusiasm was infectious. To top it all off, he was a remarkably generous person,” Dr. Kliewer said. “I will miss him terribly.”
Born and raised in the Mojave Desert town of Kingman, Arizona, Dr. Mangelsdorf earned a Bachelor of Science in biology and chemistry from Northern Arizona University in Flagstaff (1981) and his Ph.D. in biochemistry from the University of Arizona in Tucson (1987), where he and colleagues successfully cloned the gene for the vitamin D receptor. During postdoctoral studies at the Salk Institute, he defined the orphan nuclear receptor RXR and its ligand, 9-cis retinoic acid. He later characterized ligands and physiologic functions for several mammalian orphan receptors, including the oxysterol receptors (LXRs), the bile acid receptor (FXR), and the dafachronic acid receptor (DAF-12), that govern survival strategies in nematodes.
Dr. Mangelsdorf joined UT Southwestern in 1993 and became Chair of Pharmacology in 2006. He was recruited to UTSW by Nobel Laureate Alfred Gilman, M.D., Ph.D., his predecessor as Chair.
“When I saw Dallas – the city and the University – it went from not even being on my radar to the top of my list,” Dr. Mangelsdorf said in a 2010 profile published in the journal PNAS. “The environment for fostering scientific potential was astounding.”
In 2000, Dr. Mangelsdorf co-founded X-Ceptor Therapeutics Inc., a California-based biotechnology firm focused on discovering compounds that modulate nuclear receptors. The company later became part of Exelixis Inc.
Dr. Mangelsdorf’s scientific excellence was recognized with numerous prestigious awards, including the Endocrine Society’s 2025 Edwin B. Astwood Award for Outstanding Research in Basic Science and its Gerald D. Aurbach Award in 2004; the Rolf Luft Award from the Karolinska Institute for outstanding contributions in endocrinology and diabetes research (2012); the Edith and Peter O’Donnell Award in Medicine from the Texas Academy of Medicine, Engineering, Science and Technology (2007); the Transatlantic Medal from the Society for Endocrinology (2006); the Heinrich Wieland Prize from the Boehringer Ingelheim Foundation (2003); the Adolf Windaus Prize from the Falk Foundation for his work in the field of bile acid research (2000); and the John J. Abel Award from the American Society for Pharmacology and Experimental Therapeutics (1997).
Dr. Mangelsdorf is survived by his wife, Katrina Voe Cotton, M.D., Ph.D., M.B.A.; their three daughters, Laura, Sara, and Alyssa; two grandsons, James and Henry; his brothers and sister, Peter, Timothy, and Rebecca; as well as a wide circle of family and friends who mourn his loss. To share memories or a tribute, please visit the family’s memorial page.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 24 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.