Unraveling the progressive remodeling and functional exhaustion of peripheral NK cells in alcohol-related liver disease progression

초록

Background and aims: Alcohol-relateded liver disease (ALD) remains a global leading cause of liver-related mortality, yet the immunological drivers of its progression from steatosis to cirrhosis are poorly understood. While Natural Killer (NK) cells are essential for anti-fibrotic surveillance, their functional impairment is a hallmark of chronic liver injury. We sought to elucidate the high-resolution transcriptomic and functional landscape of CD56dim NK cells—the primary cytotoxic subset—across the clinical spectrum of ALD. Method: We integrated single-cell RNA sequencing (scRNA-seq) and flow cytometry to analyze peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 4), patients with alcoholic fatty liver (AFL, n = 6), and those with alcoholic cirrhosis (n = 3). A specialized computational pipeline was employed to dissect the CD56dim NK cell compartment, focusing on subset heterogeneity, functional states, and molecular programming. Results: Analysis of 7,354 high-quality CD56dim NK cells identified four transcriptionally distinct subsets, including a terminally exhausted population. Disease progression was characterized by a profound remodeling of this ecosystem, marked by a massive expansion of exhausted NK cells in cirrhotic patients. These cells exhibited a unique biphasic functional trajectory: a transient hyperactivated state during the AFL stage, followed by a collapse into terminal dysfunction in cirrhosis. Mechanistically, exhausted cells in cirrhosis established a fixed molecular program, upregulating canonical checkpoints (TIGIT, LAG3) alongside novel regulators, specifically the post-transcriptional repressor ZFP36 and the GPCRdesensitizing protein ARRB2. Conclusion: ALD progression is driven by the systematic expansion and molecular “lockdown” of an exhausted peripheral CD56dim NK cell population. This failure of anti-fibrotic surveillance, defined by a distinct biphasic trajectory, identifies ZFP36 and ARRB2 as potential therapeutic targets and offers a robust blood-based molecular signature for disease staging.