Liver disease and diabetes are among the nation’s most pressing health threats, afflicting millions of Americans. In fact, diabetes is one of the major causes of chronic liver injury. A trio of recently published journal reviews by researchers at Sanford Burnham Prebys, with colleagues elsewhere, assess the state of science, new findings and opportunities for improving diagnoses and treatments.
Hepatic stellate cells (HSCs) are a subpopulation of the liver, where they store 80 percent of the vitamin A in the body and contribute to liver development, immune responses and regeneration. The liver is the only organ in the human body that can regenerate, regrowing to normal size even after up to 90 percent of it has been removed.
But HSCs play a role in liver disease too. When the organ is damaged, they produce extracellular matrix (ECM) — a mix of proteins, minerals and other molecules that surrounds and supports cells and tissues — that serves as a protective, temporary scar to prevent further damage.
In a new review, published May 22, 2025 in Nature Reviews: Gastroenterology & Hepatology, David A. Brenner, MD, president and CEO of Sanford Burnham Prebys, and Robert F. Schwabe, MD, director of the Digestive and Liver Disease Research Center at Columbia University and a former postdoctoral fellow of Brenner, describe some of the factors that shift HSCs from their beneficial roles to the drivers of fibrogenesis — the over-accumulation of fibrous scar tissue in the liver that can chronically impair organ function and lead to cirrhosis, cancer and liver failure.
“Research has long focused on the pathofibrogenic properties of HSCs and the therapeutic reduction of ECM accumulation, but less on understanding how to prevent fibrosis by restoring HSC balance. In other words, converting pathogenic HSCs into protective HSCs,” said Brenner.
“Finding answers and new therapies is urgent. Preventable liver disease, in particular rates of metabolic dysfunction-associated steatotic liver disease or MASLD, is rising. Liver disease kills nearly 55,000 Americans each year. It’s the 10th leading cause of death, and there are currently very few effective therapies.”
The American Liver Association estimates that 4.5 million adults in the United States (1.8 percent of the adult population) have been diagnosed with liver disease, but it’s estimated that many millions more have the condition but are unaware.
Regulation of Hepatic Stellate Cell Phenotypes in Metabolic Dysfunction-Associated Steatohepatitis
In another review, published March 2025 in Gastroenterology, Brenner, Souradipta Ganguly, PhD, and Rabi Murad, PhD, at Sanford Burnham Prebys, with colleagues at University of California San Diego, examined the crucial role of HSCs in the development of liver fibrosis in metabolic dysfunction-associated steatohepatitis or MASH.
MASH is the more severe form of MASLD.
In their review, the authors describe how HSCs become activated by metabolic stress, lipotoxicity and chronic inflammation, leading to an environment that promotes fibrosis.
They note that current antifibrotic therapies target the secreted proteins of HSCs or the HSCs themselves, but suggest an alternative approach might be to induce cell death in HSC populations.
“Deletion of the entire HSC population in mice has been tested in several studies, resulting in improvement of liver fibrosis,” the authors write.
“Targeting HSCs effectively will not be simple or straightforward,” said Brenner. “There are challenges, like avoiding any reduction in liver function or suppressing liver regeneration. But the findings are encouraging and the need for new therapies paramount.”
While the rise in liver disease prevalence is alarming, it pales in comparison to the ubiquity of diabetes.
In 2021, the American Diabetes Association estimated 38.4 million Americans or 11.6 percent of the population had type 2 diabetes mellitus. Another 2 million Americans had type 1 diabetes, including about 304,000 children and adolescents. More than 1 million Americans are newly diagnosed with a form of diabetes annually.
Treatments for diabetes are diverse; managing the disease is challenging because some pharmaceutical-based therapies may pose significant risks or severe side effects. In a review published in Chemistry & Biodiversity, senior author Giau Van Vo, PhD, a postdoctoral researcher in Timothy Huang’s lab at Sanford Burnham Prebys, with colleagues in Vietnam, looked at the therapeutic potential of flavonoids to treat diabetes.
Flavonoids are a diverse group of bioactive compounds commonly found in plants and medicinal herbs. They possess antibacterial, antiviral, antioxidant, anti-inflammatory and anticarcinogenic properties. And some have demonstrated potent anti-diabetic properties, such as reducing blood glucose and enhancing insulin secretion.
“Patients with diabetes and related metabolic issues commonly use a variety of over-the-counter dietary supplements, many of which lack robust clinical data and scientific backing,” wrote Vo and his co-authors. “Herbal medicines and secondary metabolites, especially flavonoids, are emerging as promising candidates for diabetes management, owing to their various modes of action.”
But Vo and colleagues caution that much is not known about the how flavonoids precisely work and, more importantly, how to use them effectively and safely.
“There is significant potential for combination therapies, both between different flavonoids and with conventional diabetes drugs. These combinations could maximize therapeutic outcomes by targeting multiple pathways involved in diabetes pathology,” the scientists wrote, but much more research must be done.