Credit score: Pharmacological Analysis (2025). DOI: 10.1016/j.phrs.2025.107860
Metabolic dysfunction-associated steatotic liver illness is the most typical liver illness on this planet, affecting about one-third of the grownup inhabitants. This dysfunction is characterised by the buildup of fats in liver cells, which has extreme liver penalties and can be related to a excessive mortality fee from heart problems.
Now, a College of Barcelona research printed within the journal Pharmacological Analysis reveals that pemafibrate and telmisartan, two medication already authorised for different situations, successfully scale back fats accumulation in laboratory animal fashions of metabolic liver illness.
Moreover, the research means that this mixture of medication could assist to scale back each liver involvement and related cardiovascular problems. These outcomes open the door to the event of safer and more practical therapies for this illness, for which present therapeutic choices are very restricted.
The research has been carried out by a group led by Marta Alegret, professor on the UB’s School of Pharmacy and Meals Sciences, the Institute of Biomedicine of the UB (IBUB) and the CIBER Space for Physiopathology of Weight problems and Diet (CIBEROBN). The analysis was carried out in collaboration with researchers from the Santa Creu i Sant Pau Hospital Analysis Institute, the Hospital Clínic de Barcelona, the CIBER Space for Cardiovascular Illnesses (CIBERCV) and Uppsala College (Sweden).
Drug repurposing, a promising and cost-effective technique
Up to now, most new compounds studied for the therapy of metabolic dysfunction-associated steatotic liver illness (MASLD)—previously often called fatty liver illness—have failed in medical trials for a number of causes, together with security considerations. On this context, drug repurposing with a recognized and acceptable antagonistic impact profile in people is a gorgeous, secure and cheaper technique. This therapeutic repositioning is of explicit curiosity within the early, often asymptomatic, levels of the illness.
“We have focused on these phases with the aim of preventing the disease from progressing to more severe stages. But for a drug to be used in these early stages, it must have a good safety profile in humans,” explains Alegret. “That is why we have studied drugs already on the market for other pathologies, which have been shown to be very safe and could have a potential benefit in the treatment of MASLD,” she provides.
Particularly, researchers have analyzed the repurposing potential in opposition to MASLD of the only or mixed administration of a lipid-lowering drug (pemafibrate) and an antihypertensive (telmisartan), each marketed—the previous solely in Japan—for the therapy of pathologies associated to cardiovascular threat: hyperlipidemia and hypertension, respectively.
“Mortality from cardiovascular causes is significant in patients with MASLD, and often these patients also have these two risk factors together,” Alegret stresses.
Zebrafish larvae, another mannequin for finding out the illness
To verify the efficacy of the medication and discover their mechanism of motion, the researchers have utilized them to a rat mannequin of the illness and, subsequently, to a zebrafish larval mannequin. “In recent years, zebrafish have emerged as an interesting alternative model that facilitates the study of the pathophysiology of MASLD and the evaluation of treatments. These are simpler and cheaper models that allow results to be obtained more quickly and which, although they are not identical to humans, have a carbohydrate/lipid metabolism and liver physiology similar to those of mammals,” says the UB professor.
The outcomes present that the mix of the 2 medication reverses the fats accumulation within the liver induced by a food regimen excessive in fats and fructose. As well as, within the rat mannequin, the mixed administration of half a dose of pemafibrate and half a dose of telmisartan was discovered to be as efficient as a full dose of both drug in lowering fats accumulation.
“Combination therapy with drugs acting on different pathogenic pathways may be a better strategy than monotherapy, thanks to possible synergistic effects and reduced toxicity related to the use of lower doses of each drug,” Alegret factors out.
The mixture of those two medication can be helpful not just for liver illness, but in addition as a result of “it lowers blood pressure and cholesterol levels, and all this would result in a lower cardiovascular risk,” she states.
Completely different lipid-lowering mechanisms
The research additionally discovered that every drug works by completely different mechanisms and describes, for the primary time, the important thing position of the PCK1 protein in telmisartan-derived hepatic lipid reducing. “Telmisartan is a drug that has been used in other models of MASLD, but mostly in more advanced stages of the disease, and its beneficial effects have been attributed mainly to anti-inflammatory and anti-fibrotic effects. But in the early stages of the disease, there is no inflammation or fibrosis yet, only lipid accumulation,” explains the researcher.
Researchers have now discovered that the quantity of PCK1 protein within the livers of MASLD animals was lowered and that therapy with telmisartan restored its ranges to regular. “This increase in PCK1 diverts the flux of metabolites from lipid synthesis to glucose synthesis. This increase in glucose production could be negative if the glucose were exported and accumulated in the blood, as it could lead to diabetes, but we have noticed that this is not the case,” says Alegret.
Nonetheless removed from medical software
Regardless of these promising outcomes, the researchers level out that, as this can be a research utilizing animal fashions, they’re nonetheless removed from sufferers. “In order to be translated into a treatment for MASLD patients, clinical studies would be needed to show that the benefits observed in animal models also occur in humans,” says Alegret.
In any case, the outcomes increase new questions, equivalent to whether or not the medication might be equally efficient in additional superior levels of the illness, when fibrosis is current. The analysis group is due to this fact already engaged on new research in animal fashions of diet-induced liver fibrosis.
“In addition, we will develop a dual model involving liver fibrosis and cardiovascular disease to see if the beneficial action is observed not only in the liver, but also in the reduction of atherosclerosis,” she concludes.
Extra data:
Roger Bentanachs et al, Telmisartan reverses hepatic steatosis through PCK1 upregulation: A novel PPAR-independent mechanism in experimental fashions of MASLD, Pharmacological Analysis (2025). DOI: 10.1016/j.phrs.2025.107860
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Mixture of two medication that combat cardiovascular threat may additionally assist deal with the most typical liver illness (2025, September 30)
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