The liver is both one of the body’s most resilient and most mysterious organs. Like many fields of medical research, its secrets are revealed slowly, with scientific breakthroughs often requiring decades of painstaking work.
Few physician-scientists know the research long game better than Anna Mae Diehl, MD, the Florence McAlister Distinguished Professor of Medicine and director of the Duke Liver Center, who has spent her career pursuing a deceptively simple question: Why do some people recover from liver injury, while others do not?
Today, after decades of persistence and non-stop networking, Dr. Diehl has some answers, and her work is transforming the understanding of liver disease and offering therapeutic promise for millions living with metabolic dysfunction-associated steatotic liver disease (MASLD) and other forms of liver injury.
Breakthroughs
The most recent studies from her lab reveal that senescent hepatocytes—aging, non-dividing liver cells—are key drivers of inflammation and impaired regeneration in liver injury, pointing to new therapeutic targets.
In August, she, along with co-authors postdoctoral researcher David Umbaugh, PhD, and Kuo Du, PhD, assistant professor in the Division of Gastroenterology, published a review of hepatocyte senescence as an increasingly recognized contributor to liver pathophysiology.
While traditionally viewed as a state of permanent growth arrest, the authors write, hepatocyte senescence is now understood to be more dynamic and potentially reversible, particularly during liver repair. They propose reframing senescence as a continuum rather than a terminal fate.
Dr. Diehl is a senior author on a recent study, published in Nature Aging, that sparked excitement in the scientific community. The study demonstrated how liver damage caused by stress and aging might not only be slowed but potentially reversed.
The team showed how a targeted drug could restore the biological youth of diseased livers in mice—even when the animals remained on a disease-inducing diet. The findings were validated with human tissue samples, suggesting a future where age-related liver damage could be treatable.
“Liver aging is not a one-way street,” says Diehl, a 1978 graduate of Georgetown University School of Medicine and a Johns Hopkins gastroenterology trainee. “If we can understand and manipulate these mechanisms, we may be able to intervene earlier and more effectively.”
For her, liver research has always been about the long game.
The Long Game
“I’ve wanted to understand the essence of the liver — really understand what makes it work,” she adds. “We can make machines that pump blood like the heart or filter toxins like the kidneys, but we don’t have a machine for the liver. That means we have a lot more work to do. The rate at which the liver deteriorates is not carved in stone. That’s what makes this research so compelling.”
But Diehl never set out to become a researcher.
During her internship at Johns Hopkins, she was struck by the number of young patients suffering from severe alcohol-related liver disease. Even with biopsies and visual evidence, she recalls, there was no way to predict who would survive.
The experience changed the trajectory of her career, and her curiosity led her to investigate liver aging and repair, including why some patients recover from injury while others progress to liver failure. The variables, she notes, are complex—ranging from genetic and epigenetic factors to lifestyle and environment.
Recruited to Duke in 2004 to lead the Division of Gastroenterology, Dr. Diehl built a research program dedicated to understanding liver injury, repair, and regeneration. Her group was among the first to describe the role of inflammatory cytokines and immune system regulation in liver regeneration, and she pioneered research on the hedgehog signaling pathway’s role in fibrosis.
Over time, her bedside-to-bench-to-bedside model—translating clinical observations into laboratory studies and back into clinical trials—helped shape the global understanding of MASLD. Her early research demonstrated that MASLD (then called NAFLD/NASH) mimicked alcoholic liver disease in pathology, leading to its recognition as a distinct and serious condition. Today, MASLD affects roughly 25% of adults worldwide and is often linked with obesity, diabetes, and metabolic syndrome.
A Legacy of Collaboration
Her commitment to collaboration also defines Diehl’s career. She is one of the co-founding investigators in the NASH Clinical Research Network (CRN), which, over the past two decades, has advanced clinical trials and built a substantial repository of liver tissue, blood samples, and genomic data. Working with colleagues, Drs. Manal Abdelmalek and Ayako Suzuki at Duke, she spearheaded local liver biobanking efforts that now include over 1,000 samples.
Her lab has partnered with bioengineering experts like Junji Zhao, PhD, to study how blood flow influences liver regeneration, and with Duke’s Molecular Physiology Institute to leverage single-nucleus RNA sequencing for understanding sex-based differences in drug responses.
Dr. Diehl has spent much of her time convincing others to study the liver, too, because it is so central to overall health. Despite all of her scientific accomplishments, she remains a practicing physician, grounded in the relationships she builds with patients.
“I love caring for my patients,” she says. “But it’s heartbreaking that so often we have little to offer beyond palliation. That’s why research is so motivating—I want to change that.”
And after more than 30 years in research, her mission remains deeply personal as well.
“You should do your thing,” she says. “And at the end of the day, the world should be better because you did your thing.”