An international research team led by Professor Jang Hyun Choi at UNIST, working with Professor Hwayoung Yun at Pusan National University (PNU) and Professor Neung Hwa Park at Ulsan University Hospital (UUH), has identified microRNA-93 (miR-93) as a central regulator in MASLD. This marks the first time this molecule has been clearly linked to how the disease develops and progresses.

How miR-93 Disrupts Liver Function

MiR-93 is a small RNA molecule found in liver cells that controls the activity of certain genes. The researchers discovered that levels of miR-93 are unusually high in both people with fatty liver disease and in animal models. Their analysis showed that miR-93 drives fat buildup, inflammation, and scarring in the liver by suppressing SIRT1, a gene that plays a key role in managing fat metabolism inside liver cells.

To better understand its role, the team used gene editing to stop the production of miR-93 in mice. These animals showed significantly less fat accumulation in the liver, along with improved insulin sensitivity and better overall liver function. In contrast, mice engineered to produce excess miR-93 experienced more severe metabolic problems in the liver.

Vitamin B3 Emerges as a Potential Treatment

The researchers then screened 150 FDA-approved drugs to see if any could reduce miR-93 levels. Niacin (vitamin B3) stood out as the most effective option. In mice treated with niacin, miR-93 levels dropped sharply, while SIRT1 activity increased. This helped restore normal fat-processing pathways in the liver and improved overall lipid balance.

The research team explained, “This study precisely elucidates the molecular origin of MASLD and demonstrates the potential for repurposing an already approved vitamin compound to modulate this pathway, which has high translational clinical relevance.”

They added, “Given that niacin is a well-established and safe medication used to treat hyperlipidemia, it holds promise as a candidate for combination therapies targeting miRNA pathways in MASLD.”

Study Support and Publication Details

This work was supported by several organizations, including the National Research Foundation of Korea (NRF) and the Korea Research Institute of Bioscience and Biotechnology (KRIBB). The findings were published online in Metabolism: Clinical and Experimental. Key contributors include Dr. Yo Han Lee and Kieun Park from UNIST, along with Professor Joonho Jeong from Ulsan University Hospital and Jinyoung Lee from Pusan National University, who served as co-first authors.

A team at Kumamoto University, led by Associate Professor Shingo Ito, has now developed a promising solution. Their approach uses a cyclic peptide that can pass through the small intestine, known as the DNP peptide. This platform allows insulin to be delivered orally in a way that was not previously possible.

Two Effective Strategies for Intestinal Absorption

To make this work, the researchers designed two different methods to help insulin cross the intestinal barrier:

• Mixing method (interaction-based): The team combined a modified “D-DNP-V peptide” with zinc-stabilized insulin hexamers. When given orally to several diabetes models, including chemically induced (STZ mice) and genetic (Kuma mice) models, this mixture quickly brought blood sugar levels down to normal. Stable glucose control was maintained with once-daily dosing for three consecutive days.
• Conjugation method (covalent-based): Using click chemistry, the researchers attached the DNP peptide directly to insulin, creating a “DNP-insulin conjugate.” This version lowered blood sugar just as effectively as the mixing method, confirming that the peptide actively helps transport insulin through the intestine.

Lower Doses Make Oral Insulin More Practical

One of the biggest obstacles for oral insulin has been the need for extremely high doses, sometimes more than ten times higher than injections. This new platform significantly reduces that requirement. It achieved a pharmacological bioavailability of about 33-41% compared to subcutaneous injection. That level of efficiency suggests oral insulin could become far more practical for real-world use.

Future Potential for Diabetes Treatment

“Insulin injections remain a daily burden for many patients,” said Associate Professor Shingo Ito. “Our peptide-based platform offers a new route to deliver insulin orally and may be applicable to long-acting insulin formulations and other injectable biologics.”

The findings were published in the journal Molecular Pharmaceutics. The researchers are now moving forward with additional studies, including testing in larger animal models and systems that replicate the human intestine, as they work toward eventual clinical applications.

Menopause is often associated with increased weight gain and a higher risk of developing overweight and obesity. These changes can raise the likelihood of serious health problems, including cardiovascular disease and type 2 diabetes. In addition to weight gain, declining estrogen levels during menopause can trigger other changes in the body that may further increase cardiovascular risk. “This study provides important insights for developing more effective and personalized strategies for managing cardiometabolic risk in postmenopausal women,” says Regina Castaneda, M.D., postdoctoral research fellow at Mayo Clinic and first author of the study.

Exploring the Role of Hormone Therapy in Weight Loss

Hormone therapy remains the most effective first-line option for relieving common menopausal symptoms such as hot flashes and night sweats, which affect up to 75% of postmenopausal women. However, its potential role in enhancing weight-loss medications has not been well understood. Earlier studies have suggested that women using hormone therapy may lose more weight when treated with GLP-1-based drugs like semaglutide, but data on tirzepatide had been lacking.

To address this gap, researchers analyzed data from 120 adults with overweight or obesity who were treated with tirzepatide for at least 12 months. They compared outcomes between those who also used hormone therapy and those who did not, ensuring both groups had similar baseline characteristics.

Study Findings and Key Limitations

The analysis showed that women receiving both treatments lost significantly more weight. “In this observational study, women who used menopausal hormone therapy lost about 35% more weight than women taking tirzepatide alone. Because this was not a randomized trial, we cannot say hormone therapy caused additional weight loss,” says Maria Daniela Hurtado Andrade, M.D., Ph.D., endocrinologist at Mayo Clinic and senior author of the study.

“It is possible that women using hormone therapy were already engaged in healthier behaviors, or that menopause symptom relief improved sleep and quality of life, making it easier to stay engaged with dietary and physical activity changes.”

Potential Synergy Between Estrogen and GLP-1 Medications

Although more controlled studies are needed, researchers say the findings are clinically meaningful. Dr. Castaneda notes that the size of the observed difference justifies further investigation into how hormone therapy and GLP-1-based medications may work together. “The magnitude of this difference warrants future studies that could help clarify how GLP-1-based obesity medications and menopausal hormone therapy may interact. Interestingly, preclinical data suggest a potential synergy, with estrogen appearing to enhance the appetite-suppressing effects of GLP-1,” says Dr. Castaneda.

What Comes Next for Research

Future research will focus on confirming these results in randomized clinical trials and exploring whether the benefits go beyond weight loss. “Next, we plan to test these observations in a randomized clinical trial and determine if benefits extend beyond weight loss — specifically, whether hormone therapy also enhances the effects of these medications on cardiometabolic measures,” adds Dr. Hurtado Andrade. “If confirmed, this work could speed the development and adoption of new, evidence-based strategies to reduce this risk for millions of postmenopausal women navigating this life stage.”

This research was funded by the Mayo Clinic Center for Women’s Health Research.