Palmatine ameliorates MASLD in type 2 diabetes by modulating hepatic apoptosis and inflammation.

Abstract

Type 2 diabetes mellitus (T2DM) is a major risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), and their convergence presents a significant therapeutic challenge. Palmatine, an isoquinoline alkaloid with lipid-regulating and anti-inflammatory properties, is a promising candidate; however, its multi-target mechanisms remain undefined. To address this, we employed a sequential, multi-omics bioinformatics workflow to generate a testable mechanistic hypothesis, followed by rigorous experimental validation. First, integrative analyses-including target prediction, differential gene expression, pathway enrichment, and machine learning-converged to identify five core targets: ADRB2, BCL3, EGR1, FOS, and MAP3K8. Molecular docking predicted strong binding, and single-cell sequencing contextualized their expression within specific hepatic cell types. To experimentally test this predictive framework, we evaluated palmatine in a rat model of T2DM-associated MASLD. Palmatine treatment significantly improved liver function(reduced ALT, AST), attenuated inflammation (lowered TNF-α, IL-6) and oxidative stress (increased SOD, GSH; decreased MDA), ameliorated glycolipid metabolism (reduced TC, TG, LDL-C, and GLU), and reduced hepatic steatosis and fibrosis. Mechanistically, confirming the bioinformatic prediction, palmatine downregulated the expression of the five key targets and concurrently suppressed the activation of critical apoptotic executers (Caspase-3, Caspase-8, GSDME). These findings demonstrate that palmatine alleviates MASLD by modulating a novel target network to inhibit hepatocyte apoptosis, providing a robust, hypothesis-driven preclinical foundation for its therapeutic development.