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Background Metabolic dysfunction-associated steatohepatitis (MASH)-induced chronic liver diseases (CLDs) were worldwide prevalence and incidence. The stage-resolved cellular and molecular programs remained incompletely defined. This study aimed to resolve stage-specific immune and transcriptional features across CLDs processes and to identify prognostic biomarkers. Methods We integrated single-cell RNA sequencing datasets from healthy liver, MASH, cirrhosis and HCC to construct a stage-resolved cellular atlas. We performed cell-state scoring, diffusion pseudotime, gene regulatory network inference, and cell–cell interaction to decipher various macrophages and T cells transcriptional profiles. We established a method of gene sets enrichment score to detect prognostic markers and employed RNA fluorescence in situ hybridization (FISH) to validate macrophage subtype abundances and spatial interactions. Results The integrated atlas revealed the heterogeneity cell-subtype composition and transcriptional features across CLD stages. In MASH, CXCL3 + macrophage and CXCL10 + macrophage were enriched and characterized by ETS2 - and IRF1 -driven inflammatory programs that might potentially contribute to the transition from MASH to HCC. SPP1 + macrophage was exclusive to HCC and might contribute to cytotoxic T-cell (Tc) dysfunction but do not directly demonstrate functional suppression or exhaustion. Subsequently, we sought to validate the robustness of these signature genes. We integrated clinical datasets from the TCGA-LIHC to validate signature genes in HCC derived from the scRNA-seq results and identify prognostic biomarker. Survival-linked analyses uncovered SPP1 and KLF2 as prognostic biomarkers. FISH confirmed stage-specific shifts in macrophage abundances and close spatial interactions between SPP1 + macrophages and Tc in HCC specimens. Conclusion We provided a stage-resolved framework to delineated macrophage heterogeneity during CLDs progression and identified SPP1 and KLF2 as candidate prognostic biomarkers and potential therapeutic targets in HCC.
Pan et al. (Wed,) studied this question.