New Study by Dr. Nima Sharifi Reveals Common Genetics that Link to Prostate Cancer Death and Digestion
The Journal of Clinical Investigation has published research by DSUI Scientific Director Nima Sharifi, M.D., which shows HSD3B1, the most common inherited link to prostate cancer mortality, also plays an essential role in digestion.
Years after Nima Sharifi, M.D., helped discover HSD3B1, the most common inherited link to prostate cancer mortality, he and researchers at Desai Sethi Urology Institute (DSUI) found the same gene plays an essential role in intestinal physiology and digestion.
“The hyperactive HSD3B1 is extremely common. It is in the germline in about half of people of European genetic ancestry,” said Dr. Sharifi, DSUI scientific director and a member of Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine.
The National Institutes of Health-funded research, recently published in the Journal of Clinical Investigation, establishes a liver receptor, homolog-1 (LRH-1), as a central integrator of intestinal steroidogenesis and bile acid transport. The findings also implicate the LRH-1-HSD3B1-SLC10A2 network as mechanistically associated with androgen deprivation therapy (ADT) and its metabolic disturbances.
A Lesson in Cancer and Human Physiology
HSD3B1 drives testosterone biosynthesis and comes from the mother or father through inherited DNA. There’s one form that’s hyperactive, which drives resistance to hormonal therapy in prostate cancer and prostate cancer death, according to Dr. Sharifi.
Unlike most inherited cancer genes that become dysfunctional, Dr. Sharifi and colleagues suspected the widespread HSD3B1 is not dysfunctional but rather may have another, possibly beneficial, function in humans. The researchers looked at a variety of metabolites in people with different genotypes. They found that the bile acids differed in men with the variant.
Dr. Sharifi explained that, while many know the role bile acids play in digestion, most don’t know that some scientists believe bile acids are also hormones.
“When they’re done doing what they do, in terms of digestion, the vast majority of bile acids are recycled — taken back up from the gut, into blood and back to the liver,” Dr. Sharifi said.
HSD3B1 also regulates this essential link for the digestive system. The finding makes this study a starting point to discover more about how the genetics of cancer and cancer outcomes is linked to the genetics of nutrition, digestion and the gastrointestinal system.
“This started with chasing down the genetics of deadly forms of prostate cancer and finding the gene that drives the resistant and ugly form of prostate cancer that kills men,” Dr. Sharifi said. “The other side of the coin is that the same gene appears to play some other essential role in digestive physiology, which is completely surprising. Understanding this dynamic is key for future drug development because we have to understand not only how the target impacts cancer but also what else it does in the body.”
The Many Facets of These Research Findings
The study’s first author, Nikou Fotouhi, Ph.D., assistant scientist in the Sharifi Lab, will present the data at the Endocrine Society’s ENDO 2026 meeting in June in Chicago.
“One of the most exciting aspects of this work for me was realizing that the intestine is not just a passive organ, as it has traditionally been viewed, but an active regulator of hormone metabolism,” Dr. Fotouhi said.
The finding that intestinal cells can actively modify steroid hormones in ways that can contribute to systemic changes during therapy was especially striking in the setting of androgen deprivation therapy. ADT’s focus is usually on the tumor itself.
“Yet we observed broader systemic effects,” Dr. Fotouhi said. “Through this work, I came to appreciate how interconnected different organ systems are, and how processes in the intestine can influence the broader physiological context beyond the tumor. This opens new directions for understanding treatment response and improving patient outcomes.”
More from the Miller School of Medicine
Desai Sethi Urology Institute’s Dr. Nima Sharifi and Dr. Zhipeng Wang were named recipients of Prostate Cancer Foundation grants.
Speakers shared research looking at how human metabolism impacts disease at the third annual Miami Symposium on Human Metabolism.
Sylvester’s Life Sciences & Health Tech Innovation Ecosystem Summit united researchers and investors to speed cancer breakthroughs.
The Miller School of Medicine study that could explain why prostate cancer progresses despite treatment with androgen deprivation therapy.
Tags: cancer research, clinical trials, Desai Sethi Urology Institute, Dr. Nima Sharifi, Endocrine Society, endocrinology, genetics, Hormone and Metabolic Research, metabolics, prostate cancer