Progressive suppression of regulated cell death defines terminal macrophage states in liver cirrhosis.

Abstract

Macrophages are central regulators of liver immunity and fibrosis; Recent single-cell studies have characterized macrophage heterogeneity in cirrhosis; however, how regulated cell death programs shape their functional transitions across disease progression in human liver remains poorly defined. We integrated scRNA-seq data from 224,529 cells across 31 adult liver samples to define macrophage states and trajectories. Functional activities of regulated cell death pathways were assessed, and key programs were validated by dual immunofluorescence in human liver tissues. Four macrophage subsets with disease-biased distributions were identified. Cirrhotic macrophages exhibited progressive suppression of autophagy, necroptosis, apoptosis, and immunogenic cell death along differentiation, most prominently in terminal states, accompanied by transcriptional exhaustion and reduced immune regulator expression. A disease-associated transitional subpopulation displayed hybrid metabolic-immune features and yielded a six-gene diagnostic signature (LDHB, CD37, S100A10, RNASE1, CXCR4 and CORO1A) validated in bulk RNA-seq data (AUC = 0.936). Spatial analyses confirmed attenuation of autophagy and necroptosis and enrichment of CXCR4- and S100A10-positive macrophages in fibrotic niches. Human cirrhosis is characterized by progressive repression of regulated cell death programs in liver macrophages, providing mechanistic insight into disease progression and identifying macrophage-associated molecular signatures that may aid in patient stratification and serve as potential targets for future therapeutic intervention.