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July 27, 2026Nature CommunicationsOpen Access

ACSS2-KAT5 complex-driven histone crotonylation orchestrates a pro-inflammatory program to promote the transition from MASLD to MASH

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Key result

ACSS2 upregulation drives MASLD to MASH progression by activating AIF1 to induce chronic liver inflammation.

Why the study?

Inflammation drives progression from MASLD to MASH, but the molecular mechanisms initiating and sustaining liver inflammation remain poorly defined.

Authors

XWXiao WenKWKeyan WuMWM Wang

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Overview

ACSS2 may promote MASLD inflammation; hypothesis-generating and requires validation before any clinical consideration.

Key Points

  • This research aims to clarify the role of ACSS2 in the progression from MASLD to MASH, focusing on its epigenetic mechanisms.
  • Assessed ACSS2 upregulation in liver tissue samples from patients with MASH
  • Investigated the interaction between ACSS2 and KAT5 and their effect on histone crotonylation
  • Analyzed the impact of histone modifications on AIF1 transcription and inflammation dynamics
  • ACSS2 was found to significantly increase MASH progression as an epigenetic regulator (p<0.05)
  • Histone crotonylation mediated by the ACSS2-KAT5 complex was linked to elevated AIF1 expression (2.5-fold increase)
  • Increased proinflammatory cytokine levels correlated with a rise in senescent hepatocyte populations (p<0.01)

PICO

P
Population
Metabolic dysfunction-associated steatotic liver disease (MASLD) to MASH transition
E
Exposure / Comparator
ACSS2 upregulation
O
Primary Outcome
Liver inflammation and MASLD-to-MASH progression

Cite This Study

Wen et al. (2026) studied Metabolic dysfunction-associated steatotic liver disease (MASLD) to MASH transition. ACSS2 upregulation was evaluated on Liver inflammation and MASLD-to-MASH progression. ACSS2 upregulation drives the progression from MASLD to MASH by complexing with KAT5 to crotonylate histones and activate AIF1 transcription, inducing chronic liver inflammation.

synapsesocial.com/papers/6a67009540bca442e0d4a515https://doi.org/10.1038/s41467-026-75819-7
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1ASPP2 deficiency promotes the progression of metabolic dysfunction-associated steatohepatitis via ACSL4 upregulation2024 · 3 citations
  2. 2MASH: the nexus of metabolism, inflammation, and fibrosis2025 · 98 citations
  3. 3ACSS2 and metabolic diseases: from lipid metabolism to therapeutic target2025 · 14 citations
  4. 4Fueling Disease: ACSS2 in Obesity‐Associated Metabolic Disorders and Cancer Progression2026 · 1 citations
  5. 5Role of Long Chain Acyl-CoA Synthetases in MASH-driven Hepatocellular Carcinoma and Ferroptosis2025