More than 6 million adults in the United States live with metabolic dysfunction-associated steatohepatitis, or MASH, a severe form of fatty liver disease that can silently progress to cirrhosis, liver failure, and the need for a transplant. Until recently, there was no approved drug to treat it. Now, researchers at UC San Diego have published phase 2 trial results showing that an experimental injectable drug called ION224 reversed key markers of the disease over roughly one year by shutting down a single fat-producing enzyme in the liver.
The findings, published in The Lancet in early 2025, represent the strongest clinical evidence to date that silencing the gene for DGAT2, the enzyme responsible for the final step of triglyceride production in liver cells, can reduce both fat accumulation and the inflammatory scarring that makes MASH dangerous.
What the trial tested and found
The study, designated ION224-CS2, was a randomized, double-blind, placebo-controlled phase 2 trial conducted at 43 clinical sites across the United States and Puerto Rico. It enrolled 160 adults between the ages of 18 and 75, all of whom had MASH confirmed by liver biopsy and fibrosis ranging from stage F1 (mild scarring) to F3 (bridging fibrosis, one stage short of cirrhosis). The trial is registered under identifier NCT04932512 at ClinicalTrials.gov. Ionis Pharmaceuticals funded the study and supplied the drug.
Participants were randomly assigned to receive either monthly subcutaneous injections of ION224 or a matching placebo for 51 weeks. The primary endpoints were histological, meaning they were measured by examining liver tissue under a microscope rather than relying solely on blood tests or imaging. Specifically, investigators looked for resolution of steatohepatitis without worsening fibrosis, or improvement in fibrosis stage without worsening steatohepatitis. Secondary measures included changes in liver fat content by MRI, liver enzyme levels (a proxy for ongoing liver injury), and non-invasive biomarkers of scarring.
Patients who received ION224 showed reduced liver fat and decreased markers of liver injury compared with those on placebo. The trial met its primary histological endpoints, providing the first biopsy-level evidence that blocking DGAT2 with an antisense drug can meaningfully alter the tissue damage that defines MASH.
How ION224 works at the molecular level
ION224 belongs to a class of therapies called antisense oligonucleotides, short synthetic strands of modified DNA designed to bind to a specific messenger RNA and prevent it from being translated into protein. In this case, the target is the messenger RNA that codes for DGAT2, an enzyme that catalyzes the last chemical step in assembling triglycerides inside liver cells.
Think of it this way: if the liver were a factory overproducing fat, DGAT2 would be the machine on the final assembly line. ION224 does not try to slow the entire factory. It shuts down that one machine by intercepting the genetic instructions before the machine can be built.
Hepatologist Rohit Loomba, who led the UC San Diego research team, has described DGAT2 as central not only to fat buildup but also to the inflammatory cascade that scars liver tissue and drives progression from simple fatty liver to fibrotic MASH. Preclinical work from the same group, published in Science, identified DGAT2 as one of two enzymes controlling liver damage in steatohepatitis, providing the mechanistic rationale for targeting it with precision therapy rather than broad metabolic drugs.
The research that paved the way
ION224-CS2 did not emerge from a single experiment. UC San Diego’s DGAT2 research program has been building toward this result for years. An earlier phase 2 trial tested a DGAT2 antisense inhibitor in patients with non-alcoholic fatty liver disease (the older terminology for the same spectrum of conditions). That study, published in The Lancet Gastroenterology & Hepatology and indexed in PubMed, used MRI-based measurement of liver fat as its primary outcome rather than biopsy.
That earlier trial showed dose-dependent reductions in hepatic triglyceride content over several months without major safety signals. Its design and eligibility criteria are documented in the corresponding ClinicalTrials.gov listing. While the imaging-based approach was less definitive than biopsy, it established that DGAT2 inhibition could substantially reduce liver fat in humans, justifying the move to a histology-driven trial in patients with confirmed MASH and fibrosis.
The progression from imaging endpoints to biopsy endpoints matters because histological assessment remains the gold standard for evaluating whether a drug truly modifies MASH. Reducing fat on an MRI scan is encouraging, but regulators and liver specialists want to see changes in the tissue itself: less inflammation, less ballooning of liver cells, and ideally, regression of fibrosis.
Where ION224 fits in a changing treatment landscape
For decades, MASH had no FDA-approved pharmacologic treatment. That changed in March 2024, when the agency granted accelerated approval to resmetirom (brand name Rezdiffra), a thyroid hormone receptor agonist developed by Madrigal Pharmaceuticals. Resmetirom works through a completely different mechanism: it activates a receptor in liver cells that speeds up fat metabolism and increases energy expenditure, essentially telling the liver to burn more fat rather than store it.
Resmetirom’s approval was a milestone, but it came with conditions. The accelerated pathway requires a confirmatory phase 3 trial to verify long-term clinical benefit, and the drug is indicated specifically for adults with MASH and moderate to advanced fibrosis (stages F2 and F3) who are also managing weight. As of June 2026, resmetirom remains the only approved drug in the space, making it the default comparator for every experimental therapy in the pipeline.
No head-to-head trial has compared ION224 against resmetirom. The two drugs attack MASH from opposite directions: one accelerates fat burning, the other blocks fat production. Whether DGAT2 blockade delivers broader histologic reversal, fewer side effects, or complementary benefits when combined with resmetirom is a question only larger comparative studies can answer.
GLP-1 receptor agonists, the drug class behind semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), add another layer of complexity. These drugs are already being studied for their effects on liver fat and fibrosis, largely as a consequence of the dramatic weight loss they produce. If future trials show that ION224 delivers additive fibrosis regression when combined with GLP-1 drugs or resmetirom, the treatment approach for MASH could shift toward multidrug regimens tailored to individual risk profiles. For now, that possibility remains theoretical.
What the trial cannot tell us yet
Several important questions remain unanswered. A 51-week trial can capture injection-site reactions, liver enzyme fluctuations, and short-term adverse events, but it cannot rule out cardiovascular, metabolic, or oncologic risks that might surface over years of treatment. Antisense oligonucleotides can, in some settings, trigger immune responses or off-target gene silencing, and extended follow-up data beyond the trial period have not been reported.
Durability is another open question. It is not yet clear whether the histologic improvements observed at week 51 persist after treatment stops, plateau with continued dosing, or require indefinite therapy to maintain. Phase 3 programs and extension studies will need to address whether lower or less frequent dosing could preserve benefits while reducing cost and potential side effects.
Generalizability also deserves scrutiny. The trial excluded patients with cirrhosis (stage F4), decompensated liver disease, and significant competing conditions such as advanced kidney impairment or unstable cardiovascular disease. Real-world MASH populations are often older, sicker, and more medically complex than phase 2 cohorts. How DGAT2 antisense therapy performs in those patients remains unknown.
Finally, the full granularity of the trial data, including exact response rates, subgroup analyses by fibrosis stage, and detailed safety tables, sits behind the Lancet paywall and supplementary appendix. The publicly available abstract and ClinicalTrials.gov record provide the broad strokes but not the fine detail that independent analysts need to fully evaluate the drug’s risk-benefit profile.
What this means for patients watching the MASH pipeline
For the millions of people living with MASH, the ION224 data represent a credible signal that a new class of targeted therapy can reverse the tissue-level damage that drives the disease. The trial’s use of biopsy-confirmed endpoints, randomized placebo control, and preregistered design place it near the top of the evidence hierarchy for a mid-stage study.
But a phase 2 trial is not a finished answer. It is a proof of concept strong enough to justify the larger, longer, and more expensive phase 3 trials that regulators require before approving a new drug. Until those results arrive, ION224 remains an experimental therapy best pursued within clinical trials, not a treatment patients can request from their doctors.
What the UC San Diego findings do establish is that MASH is no longer a disease without therapeutic targets. Between resmetirom’s conditional approval, the GLP-1 agonists under investigation, and now a precision antisense drug aimed at a single fat-producing enzyme, the pipeline is deeper and more mechanistically diverse than at any point in the history of liver disease research. For patients and clinicians alike, the practical question is shifting from “Is there anything we can do?” to “Which combination of tools will work best for each individual?”
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*This article was researched with the help of AI, with human editors creating the final content.
