The research, published on October 17, 2025, in Communications Medicine, questions the long-standing use of body-mass index (BMI) as a reliable indicator of obesity and heart risk. It offers new evidence that the fat people cannot see may be just as dangerous as the weight they can.

Going Beyond BMI to Understand True Health Risks

Visceral fat (which surrounds internal organs) and hepatic fat (fat stored in the liver) have long been associated with Type 2 diabetes, high blood pressure, and heart disease. However, their direct impact on artery health had not been well established until now.

Using advanced MRI scans and data from more than 33,000 adults in Canada and the United Kingdom, the researchers discovered that higher levels of visceral and liver fat were closely tied to thickening and clogging of the carotid arteries in the neck. These arteries carry blood to the brain, and when they narrow, they increase the risk of stroke and heart attack.

"This study shows that even after accounting for traditional cardiovascular risk factors like cholesterol and blood pressure, visceral and liver fat still contribute to artery damage," says Russell de Souza, co-lead author of the study and associate professor in the Department of Health Research Methods, Evidence, and Impact at McMaster.

Hidden Fat Adds Risk Even in the Absence of Other Factors

"The findings are a wake-up call for clinicians and the public alike," says de Souza, a faculty member in the Mary Heersink School of Global Health and Social Medicine, and member of the Centre for Metabolism, Obesity and Diabetes Research (MODR) and at McMaster, the results should prompt both doctors and patients to pay attention to hidden fat, not just visible weight. He led the research with co-author Marie Pigeyre, associate professor in McMaster's Department of Medicine.

The analysis drew from two major population studies: the Canadian Alliance for Healthy Hearts and Minds (CAHHM) and the UK Biobank. MRI scans were used to measure fat distribution and artery condition. The team found that visceral fat was consistently associated with plaque buildup and artery wall thickening, while liver fat had a smaller but still important effect. These relationships remained significant even after adjusting for lifestyle habits and metabolic risk factors such as diet, exercise, and cholesterol.

Rethinking How We Measure Obesity

The findings highlight the need for clinicians to look beyond BMI or waist measurements when assessing heart risk. Imaging tests that reveal fat stored around internal organs may offer a more accurate picture of cardiovascular health.

For people in midlife, the study is a reminder that even a normal weight does not guarantee a healthy heart. Hidden fat can quietly increase the risk of serious disease without obvious physical signs.

"You can't always tell by looking at someone whether they have visceral or liver fat," says Sonia Anand, corresponding author of the study, a vascular medicine specialist at Hamilton Health Sciences and professor in the Department of Medicine at McMaster. "This kind of fat is metabolically active and dangerous; it's linked to inflammation and artery damage even in people who aren't visibly overweight. That's why it's so important to rethink how we assess obesity and cardiovascular risk."

This research was supported by the Canadian Partnership Against Cancer, Heart and Stroke Foundation of Canada, and the Canadian Institutes of Health Research, with additional contributions from the Population Health Research Institute, Montreal Heart Institute, Sunnybrook Health Sciences Centre, and others. MRI reading costs were supported in-kind by Sunnybrook Hospital, and Bayer AG provided IV contrast. The study also drew on data from the Canadian Partnership for Tomorrow's Health and the PURE Study.

Their study, published in Nature Communications, reveals that RNA, typically known for transmitting genetic messages, can be hijacked to build liquid-like "droplet hubs" inside the cell nucleus. These droplets act as command centers that activate growth-related genes. The team not only observed this phenomenon but also developed a molecular switch that can dissolve these hubs on demand, effectively cutting off the cancer's growth mechanism at its core.

RNA Becomes Cancer's Builder

The researchers focused on a rare kidney cancer called translocation renal cell carcinoma (tRCC), which primarily affects children and young adults and currently lacks effective treatments. This cancer results from TFE3 oncofusions -- abnormal hybrid genes created when chromosomes break and fuse incorrectly.

Until now, scientists did not fully understand how these fusion proteins made tRCC so aggressive. The Texas A&M team found that the fusions enlist RNA to serve as a structural framework. Instead of merely carrying messages, RNA molecules assemble into droplet-like condensates that cluster vital molecules together. These droplets then act as transcriptional hubs, activating genes that promote tumor growth.

"RNA itself is not just a passive messenger, but an active player that helps build these condensates," said Yun Huang, PhD, professor at the Texas A&M Health Institute of Biosciences and Technology and senior author.

The team also identified an RNA-binding protein called PSPC1, which stabilizes these droplets and makes them even more effective at driving tumor formation.

Mapping the Hidden Machinery of Cancer

To uncover how this process works, the researchers used a suite of cutting-edge molecular biology tools:

• CRISPR gene editing to "tag" fusion proteins in patient-derived cancer cells, letting them track exactly where these proteins go.
• SLAM-seq, a next-generation sequencing method that measures newly made RNA, showing which genes are switched on or off as the droplets form.
• CUT&Tag and RIP-seq to map where the fusion proteins bind DNA and RNA, revealing their precise targets.
• Proteomics to catalog the proteins pulled into the droplets -- pinpointing PSPC1 as a key partner.

By layering these techniques, the researchers built the clearest picture yet of how TFE3 oncofusions hijack RNA to build cancer's growth hubs.

Dissolving the hubs that drive tumors

Discovery alone wasn't enough. The team wanted to know: If the droplets are cancer's engine, can we shut them down?

To test this, they engineered a nanobody-based chemogenetic tool -- essentially a designer molecular switch. Here's how it works:

• A nanobody (a miniature antibody fragment) is fused with a dissolver protein.
• The nanobody locks onto the cancer-driving fusion proteins.
• When activated by a chemical trigger, the dissolver melts the droplets, breaking the hubs apart.

The result? Tumor growth ground to a halt in both lab-grown cancer cells and mouse models.

"This is exciting because tRCC has very few effective treatment options today," said Yubin Zhou, MD, PhD, professor and director of the Center for Translational Cancer Research. "Targeting condensate formation gives us a brand-new angle to attack the cancer, one that traditional drugs have not addressed. It opens the door to therapies that are much more precise and potentially less toxic."

Beyond Kidney Cancer: A New Therapeutic Model

For the research team, the most powerful part of the study wasn't just watching RNA build these hubs but seeing that they could be dismantled.

"By mapping how these fusion proteins interact with RNA and other cellular partners, we are not only explaining why this cancer is so aggressive but also revealing weak spots that can be therapeutically exploited," said Lei Guo, PhD, research assistant professor at the Institute of Biosciences and Technology.

Because many pediatric cancers are also driven by fusion proteins, the implications extend far beyond tRCC. A tool that can dissolve these condensates could represent a general strategy to cut off cancer's engine rooms at the source.

Why this matters

tRCC represents nearly 30% of renal cancers in children and adolescents, yet treatment choices remain scarce and outcomes are often poor. This breakthrough provides both an explanation for how the cancer organizes its molecular machinery and a potential way to dismantle it.

"This research highlights the power of fundamental science to generate new hope for young patients facing devastating diseases," Huang added.

Just as cutting power to a coworking hub halts all activity, dissolving cancer's "droplet hubs" could stop its ability to grow. By revealing how RNA builds these structures -- and by finding a way to take them apart -- Texas A&M Health researchers have opened a promising new path toward treating one of the most challenging childhood cancers.

The research team created a strategy to block the activity of PCSK9, a protein that plays a crucial role in controlling the amount of low-density lipoprotein cholesterol (LDL-C), often called "bad" cholesterol, in the bloodstream. This innovative approach relies on molecules called polypurine hairpins (PPRHs), which help cells absorb more cholesterol and prevent its accumulation in arteries, without producing the side effects often linked to statin drugs.

The study, published in Biochemical Pharmacology, was led by professors Carles J. Ciudad and Verònica Noé of the University of Barcelona's Faculty of Pharmacy and Food Sciences and the Institute of Nanoscience and Nanotechnology (IN2UB), in collaboration with Nathalie Pamir from the University of Oregon in Portland (United States). Funding came from Spain's Ministry of Science, Innovation and Universities (MICINN) and the U.S. National Institutes of Health (NIH).

Targeting the PCSK9 Protein

PCSK9 (protein convertase subtilisin/kexin type 9) has become a major target for cholesterol treatment and cardiovascular protection over the past decade. This enzyme binds to receptors on cell surfaces that normally capture LDL cholesterol. When PCSK9 binds to these receptors, it reduces their number, leading to higher LDL cholesterol levels circulating in the blood and increasing the risk of hypercholesterolemia.

The new technique developed by the team uses PPRHs to halt the transcription of specific genes, effectively silencing their expression. In this study, PPRHs were used to inhibit the PCSK9 gene, resulting in an increase in LDL receptors (LDLR) and improved cholesterol uptake by cells. This mechanism helps reduce both circulating cholesterol and the risk of plaque buildup in arteries.

How Polypurine Hairpins Work

PPRHs are single-stranded DNA molecules, known as oligonucleotides, that can bind precisely to complementary DNA or RNA sequences. The research demonstrated for the first time that two specific PPRHs, HpE9 and HpE12, lower PCSK9 RNA and protein levels while raising LDLR levels.

"Specifically, one of the arms of each chain of the HpE9 and HpE12 polypurines binds specifically to polypyrimidine sequences of exons 9 and 12 of PCSK9, respectively, via Watson-Crick bonds," notes Professor Carles J. Ciudad, from the Department of Biochemistry and Physiology. This binding inhibits gene transcription and the action of RNA polymerase or the binding of transcription factors.

The new therapeutic technique has been validated in vivo in transgenic mice expressing the human PCSK9 gene. "The results show that both HpE9 and HpE12 are highly effective in HepG2 cells. HpE12 decreases PCSK9 RNA levels by 74% and protein levels by 87%. In the case of transgenic mice, a single injection of HpE12 reduces plasma PCSK9 levels by 50% and cholesterol levels by 47% on the third day," says Professor Verònica Noé.

Toward Statin-Free Cholesterol Control

Since PCSK9 was defined as a significant target in plasma cholesterol-lowering therapy, several therapeutic approaches have been designed to lower or block its action. For example, gene silencing with siRNAs, antisense oligonucleotides or the CRISPR technique. In particular, Inclisiran, an siRNA agent against PCSK9, and the monoclonal antibodies such as evolocumab and alirocumab stand out.

"PPRHs, especially HpE12, are therapeutic oligonucleotides with many advantages, including low cost of synthesis, stability and lack of immunogenicity. In addition, such a PPRH-based approach against PCSK9 would not lead to side effects such as the myopathies associated with statin therapy," the experts conclude.