New preclinical research suggests that palmatine may reduce diabetes-related fatty liver disease by targeting inflammation, oxidative stress, and liver cell death across multiple biological pathways.
Research: Palmatine improves MASLD in type 2 diabetes by modulating liver apoptosis and inflammation. Image credit: sasirin pamai / Shutterstock
In a recent study published in the journal scientific reportA group of researchers investigated how palmatine, a natural chemical found in some medicinal plants, improves MASLD by controlling apoptosis and inflammation in T2DM.
Burden of MASLD in patients with type 2 diabetes
Did you know that more than half of T2DM patients also develop MASLD? The dual burden increases liver damage and increases the likelihood of developing cirrhosis and cardiovascular complications.
Fatty liver disease is more than just an accumulation of fat in the liver. It also causes inflammation, insulin resistance, and liver cell damage. Standard treatments target only part of the disease mechanism and are therefore less effective. Therefore, there is interest in discovering naturally occurring compounds that can provide multiple targets.
To do this, researchers need to understand the actions of these natural compounds at the cellular and molecular level, and further research should explore integrative therapeutic options through the use of natural compounds.
Bioinformatics and experimental research design methods
This study combined bioinformatics analysis and experimental validation to investigate the effects of palmatine. First, drug targets were identified using databases such as Chinese Herbal Medicine System Pharmacology, PharmMapper, HERB, and SymMap. Disease-related genes related to MASLD and apoptosis were obtained from GeneCards.
These datasets were merged and overlapping targets were identified. Data from the Gene Expression Omnibus database on gene expression was analyzed using R software and predefined statistical criteria were used to determine which genes were differentially expressed.
Significant genes were identified using 10 machine learning techniques, with random forest and decision tree models ultimately providing the best balance between predictive performance and feature importance.
Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were used to examine the biological pathways associated with the identified genes, and single-cell sequencing was performed to determine gene expression patterns at the individual cell level.
This study also incorporates analysis of immune infiltrates, cell death patterns, pseudotime, and RNA rates to better understand the context of candidate targets within the liver microenvironment.
To verify this finding, we created a T2DM-related MASLD model in rats using both high-fat diet and streptozotocin injection, and assigned rats to blank, model, semaglutide, and low-, intermediate-, and high-dose palmatine groups. Treatment was then administered for 4 weeks.
Discovery of key molecular targets and pathways
Integrated bioinformatics analysis identified 138 overlapping targets between palmatin and MASLD, which were further narrowed down to 43 significant genes through differential expression analysis. Functional enrichment revealed that the major pathways of these genes are lipid metabolism, inflammatory response, and apoptosis.
Machine learning models consistently identified five core targets: adrenergic receptor beta 2 (ADRB2), B-cell lymphoma 3 (BCL3), early growth response 1 (EGR1), Fos proto-oncogene (FOS), and mitogen-activated protein kinase kinase 8 (MAP3K8).
Molecular docking showed that palmatine has very high binding affinity for all the above proteins. Therefore, this supports the plausibility that palmatin may be directly involved in them.
Moreover, single-cell sequencing provided further evidence that these genes exhibit cell type-specific expression patterns across several hepatocyte populations, suggesting that these genes may regulate immune and liver-related functions. More extensive single-cell analysis further suggested a dynamic role for these targets within the liver immune microenvironment.
Improving metabolism and liver function in rats
In experimental models, rats with T2DM-associated MASLD exhibited significant metabolic disturbances, including elevated glucose, lipid, and inflammatory markers. The activity of liver enzymes such as alanine aminotransferase and aspartate aminotransferase was also analyzed, and increased levels of these liver enzymes indicate that they are markers of liver damage.
Palmatine treatment lowered blood sugar, total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Decreased alanine aminotransferase and aspartate aminotransferase. Reduction of malondialdehyde. Increased antioxidant markers such as superoxide dismutase and glutathione.
Liver improvement at histological and cellular level
In untreated model rats, the liver showed inflammatory tissue changes with severe fat accumulation and fibrosis, whereas in palmatine-treated rats, the liver structure was improved, with fewer lipid droplets and less collagen deposition. These improvements were dose-dependent, with histopathological analysis showing the most significant reduction in hepatic steatosis in the intermediate-dose group.
Palmatine decreased the expression of ADRB2, BCL3, EGR1, FOS, and MAP3K8 at the molecular level, as well as apoptotic proteins such as caspase-3, caspase-8, and gasdermin E. This finding indicates an overall reduction in hepatocyte death as evidenced by immunofluorescence and protein analysis, consistent with bioinformatics predictions.
In addition to its pleiotropic actions promoting liver health through several pathways involved in metabolism, inflammation, and apoptosis, palmatine also exerts anti-inflammatory effects by suppressing the production of various pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-6.
Treatment possibilities and research limitations
Palmatine has shown therapeutic potential in managing MASLD associated with T2DM by targeting multiple biological pathways, thereby improving metabolic parameters, reducing inflammation, and suppressing markers of hepatocyte apoptosis.
These multilevel effects make them promising candidates for the treatment of complex metabolic diseases where single-targeted therapies often fail. However, this is a preclinical study in rats, and by targeting both liver damage and systemic metabolic dysfunction, palmatine may help develop future treatments for people at high risk of progressive liver disease. Its safety, efficacy, and clinical use require further clinical validation.
Reference magazines:
- Yang, H., Shi, Z., Qi, Y., Bao, S., Li, C., Mei, J., Sun, M., Han, Y., Ma, B. (2026). Palmatine improves MASLD in type 2 diabetes by regulating liver apoptosis and inflammation. Science Parliament DOI: 10.1038/s41598-026-45476-3, https://www.nature.com/articles/s41598-026-45476-3
