Systems-level identification of conserved molecular drivers underlying the progression of alcoholic hepatitis and alcoholic cirrhosis and their therapeutic modulation by S-adenosyl-L-methionine.

Alcohol-associated liver disease (ALD) encompasses a progressive spectrum of hepatic injury, with alcoholic hepatitis (AH) and alcoholic cirrhosis (AC) representing clinically severe and mechanistically interconnected stages. Despite significant disease burden, therapeutic strategies targeting core molecular drivers of disease progression remain limited. Identifying conserved regulatory determinants across AH and AC may provide a rational framework for mechanism-driven therapeutic intervention. S-adenosyl-L-methionine (SAMe), a key metabolic intermediate involved in methylation and redox homeostasis, has shown hepatoprotective potential; however, its direct molecular targets in ALD remain poorly characterized. An integrative in silico framework was employed to identify conserved molecular signatures and evaluate SAMe-target interactions. Publicly available transcriptomic datasets from the NCBI Gene Expression Omnibus (GEO) were analysed to identify differentially expressed genes (DEGs) in AH and AC, followed by Venn-based intersection to determine shared DEGs. Functional enrichment (GO and KEGG) and protein-protein interaction (PPI) network analyses were conducted to identify key regulatory hub genes. Selected hub proteins were subjected to molecular docking with SAMe and the stability of the resulting protein-ligand complexes was further evaluated using 100ns molecular dynamics (MD) simulations in conjunction with MM/GBSA binding free energy calculations. This integrative analysis identified 826 shared DEGs enriched in pathways associated with intracellular signalling, transcriptional regulation and extracellular matrix (ECM) organization. Network analysis revealed TGFB1, COL1A2, ESR1, PDGFRA, LUM and BCL2 as central hub genes. Molecular docking demonstrated favourable binding interactions of SAMe with these targets, with TGFB1 exhibiting the highest binding affinity (-7.0 Kcal/mol). MD simulations confirmed stable conformational dynamics of SAMe-bound complexes, particularly TGFB1, characterized by reduced structural fluctuations, increased compactness and sustained hydrogen bonding. Binding free energy analysis further supported the thermodynamic stability of these interactions, with the TGFB1-SAMe complex showing the most favourable energy profile. Collectively, these findings identify conserved molecular signatures linking AH and AC and suggest potential molecular interactions between SAMe and key regulatory proteins implicated in disease progression. By integrating transcriptomic, network and structural analyses, this study provides a systems-level framework for understanding the molecular landscape of ALD and offers a basis for future experimental studies aimed at evaluating therapeutic strategies targeting shared disease determinants.