Jan. 24, 2025
When the Sterols Align
University of Pittsburgh researchers discover how dysfunction in cells' garbage disposal-like lysosomes contribute to inflammation and increased mortality risk in pulmonary arterial hypertension—revealing potential treatment targets.
TOPICS: Cardiovascular | Chronic Disease | School of Medicine
Designs on Aging-Ready
By Phoebe Ingraham Renda
Lysosomes, often described as cellular stomachs, break down cell waste using their acidic interiors. But lysosomes also play roles in cholesterol metabolism, cellular signaling and antigen presentation. Dysfunctional lysosomes are linked to many diseases—and now, pulmonary arterial hypertension (PAH) joins that list, according to a 2025 study in Science led by University of Pittsburgh researcher Stephen Chan.
Chan, Vitalant Professor of Vascular Medicine in the School of Medicine, was intrigued by the connection between lysosomal dysfunction and atherosclerosis, a vascular inflammatory disease, and wondered if similar mechanisms were at play in PAH, which also involves inflammation in lung blood vessels.
“We know that inflammation is helpful in both health and disease, but we don't understand the molecular levers and tools that cells use to control it,” says Chan.
In the study, Chan’s team, including lead author Lloyd Harvey, found that lysosomal dysfunction directly contributes to PAH. When lysosomes fail to acidify, they can’t properly metabolize cholesterol, leading to the release of inflammatory molecules like oxysterols and bile acids. A key player in this process is the NCOA7 protein, which regulates lysosomal acidification.
“We know that inflammation is helpful in both health and disease, but we don't understand the molecular levers and tools that cells use to control it.”
Stephen Chan, Vitalant Professor of Vascular Medicine
Using lab and animal models, the researchers showed that without active NCOA7, lysosomes lose their acidity, triggering cholesterol mismanagement and inflammation.
“Our work uncovered that inflammation depends upon how cholesterol is sorted in the lysosome and how it is made into these oxidized forms—it’s a link that tells us a lot about how inflammation in the body develops and is controlled,” Chan explains.
In parallel, Chan and collaborators in San Diego were conducting a clinical metabolomics study of more than 2,500 PAH patients, searching for blood markers linked to mortality risk. They identified several uncharacterized metabolites using mass spectrometry. With help from chemical biologists and medicinal chemists, they discovered these metabolites were oxysterols—the same inflammatory molecules from the lysosome study.
Digging deeper, the team examined genetic variants of NCOA7 and found one, called the C allele, linked to higher mortality in PAH patients. Individuals with the CC genotype had the highest risk. Cell studies confirmed that this allele reduced NCOA7 expression, impairing lysosomal acidification and increasing inflammation.
“We were uncovering a pathway that, at least in part, is determining how likely and how quickly a person is going to die from pulmonary hypertension,” says Chan.
These findings suggest that the C allele and plasma oxysterols could serve as biomarkers for identifying high-risk patients.
To explore therapeutic potential, Chan partnered with computational biologist Ivet Bahar, of Stony Brook University, who used an artificial intelligence pipeline to identify small molecules that could activate NCOA7. One candidate showed promise in cell models and improved inflammation in a rodent PAH model.
Chan predicts this genetic-metabolic-inflammatory pathway could apply to other diseases, particularly in the aging population.