The liver’s job clearing harmful substances from the body is so essential that the organ may have implications for addressing unexpected diseases, including Alzheimer’s and heart disease. A promising example comes from new Keck School of Medicine of USC research published in the Journal of Biological Chemistry .
The study, conducted in aged rats, shows that an experimental drug called cinaciguat reverses effects of aging in the liver. This, in turn, may lower risk for Alzheimer’s disease and clogged arteries. The researchers also revealed what’s behind that rejuvenation, including a specific biochemical pathway used for local communication between liver cells, which suggests a potential therapeutic target.
“We need to do further translational work to see whether our findings might point to new therapies,” said corresponding author Laurie DeLeve, MD, PhD , professor and vice chair for scientific affairs in the USC Department of Medicine . “We’re hopeful, though, because the findings line up with a lot of epidemiological results showing age as a major risk factor for Alzheimer’s and atherosclerosis, and liver damage as a risk factor for Alzheimer’s.”
More broadly, the research suggests that medicating the liver may be a new path for preventing some of the most serious diseases associated with aging. This approach could make a big difference for Alzheimer’s, as treatments in the brain have a 98% failure rate in clinical trials.
“If we’re right that the liver is impactful, what do we do about that?” said first author Sam de Leve, MA, a USC lab technician and child of Laurie DeLeve. “Rather than trying to get a drug through the blood-brain barrier, which is obnoxiously difficult, we could direct drugs to the liver, an organ where there might be more therapeutic impact and certainly an easier job of drug delivery.”
In the study, the researchers examined a little-studied population of liver cells, called liver sinusoidal endothelial cells (LSECs). These cells, which line the blood vessels of the liver, are shot through with holes, like tiny sieves. The holes allow larger molecules in the circulation to reach hepatocytes — cells that do the lion’s share of the liver’s work clearing compounds from the body.
In normal aging, the LSEC holes shrink and close up over time, leaving bigger molecules in circulation.
The investigators followed up on observations about how aging curtails the liver’s ability to clear one of these larger molecules, amyloid beta. This molecule forms plaques in the brain associated with Alzheimer’s disease. The team hypothesized that the shrinking portals in LSECs may explain increased circulation of amyloid beta with age.
Experiments compared aged mice treated with cinaciguat for two weeks to a couple of untreated control groups, one aged and the other young. The drug rejuvenated LSECs, reopening the pores and restoring the cells’ ability to clear substances from the body. Amyloid beta levels in treated rats were cut in half, dropping to the same levels as in young rats, while untreated aged rats showed no decrease.
The researchers also measured low-density lipoproteins (LDL), the so-called “bad” cholesterol that builds up in arteries and leads to heart disease. The LDL was supposed to serve as a control because those particles are actually so small that they don’t require holes in the LSECs to leave circulation.
According to the original hypothesis, LDL levels in aged rats who received cinaciguat should have remained unchanged. Instead, they dropped to the same levels as in young rats.
“We said, ‘Wait, why did that go down? Clearly, there’s more to this story,’” Sam de Leve said.
Based on the observation that hepatocytes perform better in the presence of LSECs, the team began investigating the crosstalk between these two cell types. They uncovered a previously unknown biochemical chain reaction controlling local communication between liver cells.
Cinaciguat activates a molecular messenger called soluble guanylate cyclase in LSECs. This spurs them to release a specific growth factor, called HB-EGF, that boosts hepatocytes. Specifically, this growth factor prompts hepatocytes to change their cell surfaces to grab onto LDL and amyloid beta.
With age, LSECs lose the ability to release the growth factor, but cinaciguat restored that capacity.
In addition to the discovery about cellular crosstalk in the liver, this study is the first to show that a drug can fully restore shape and function to LSECs, including their clearance capacity. It’s also the first to demonstrate a liver-directed treatment that normalizes amyloid beta and LDL levels elevated in aging.
The results indicate that cinaciguat, or a related drug, has potential for reversing the effects of aging in the liver and preventing Alzheimer’s and heart disease. There may also be future opportunities to develop drugs to target HB-EGF.
The team will continue this line of inquiry in rats. They aim to test whether lowering amyloid beta with cinaciguat translates to measurable results preventing Alzheimer’s.
The authors also anticipate that their study’s implications will spark the curiosity of scientists in other disciplines.
“We hope that people who are in fields like atherosclerosis research read this, and want to grab the idea for themselves,” Sam de Leve said. “There are six different ways someone could go with this, and we can’t do them all. So please, scoop us. We’d love it.”
Other co-authors of the study are Xiangdong Wang, Helia Alavifard and Lily Dara, all of the Keck School of Medicine of USC.
The research was federally funded by the National Institutes of Health [R56AG071480, 5R01DK100580].
Journal of Biological Chemistry
Experimental study
Animals
Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL
26-Sep-2026
The authors declare that they have no conflicts of interest with the contents of this article.