A conserved immunometabolic transcriptional programme defines MASLD progression and is maintained in hepatocellular carcinoma

Metabolic dysfunction–associated steatotic liver disease (MASLD) constitutes a primary cause of hepatocellular carcinoma (HCC). However, the transcriptional programs linking disease progression to tumor biology remain incompletely defined. Here, we aimed to identify conserved transcriptional programs underlying MASLD progression and to determine their biological organization, cellular context, and relevance in hepatocellular carcinoma. To accomplish this, we used an integrative analytical scheme across independent cohorts, including bulk liver transcriptomic datasets spanning disease stages (n = 63 and n = 170), clinical validation in the TCGA-LIHC cohort (n = 423), single-cell transcriptomic mapping, and external validation. Through this approach, we identified a coordinated immunometabolism transcriptional program associated with disease progression, encompassing 2,255 genes and enriched for metabolic and immune signaling pathways. Furthermore, immune profiling revealed structured remodeling, characterized by attenuation of global immune activity and redistribution of immune cell populations across disease stages. Network analysis uncovered a densely interconnected transcriptional module with central hub genes, denoting a coordinated regulatory architecture. Finally, cross-cohort validation identified a conserved core set of twenty-two genes that were reproducibly associated with disease progression. This program was preserved across independent datasets and persisted in hepatocellular carcinoma. Furthermore, it exhibited heterogeneous activation and modest prognostic value. In addition, single-cell analysis localized transcriptional activity to hepatocytes, endothelial cells, and macrophages, thereby defining a multicellular axis underlying disease progression. Collectively, these findings demonstrate that MASLD progression is a conserved immunometabolic transcriptional program that spans disease stages and malignancy.