---
title: "Lysine acylation and its potential role in metabolic and inflammatory processes in MASLD"
id: "frontiers-in-immunology-19-the-role-of-lysine-acylation-in-metabolic-dysregulation-and-inflammatory"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-19-the-role-of-lysine-acylation-in-metabolic-dysregulation-and-inflammatory"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1933792"
published_at: "2026-09-03T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Lysine acylation and its potential role in metabolic and inflammatory processes in MASLD
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1933792)
- **Published At:** 2026-09-03T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source page contains site and journal navigation material but does not include the article text, figures, methods, or results for the article titled about **lysine acylation** in the **MASLD** hepatic immune microenvironment. - Publication metadata (journal name Frontiers in Immunology and article URL) was visible, but core content such as abstract, introduction, methods, results, discussion, and conclusions were not present in the supplied source. - Because the article body was not provided, specific experimental findings, mechanistic details, measured endpoints, sample sizes, or author conclusions were not available and therefore cannot be summarized or restated. - The absence of article content prevents reporting on any clinical or translational implications, biomarker data, therapeutic targets, or pathway-specific evidence related to lysine acylation and hepatic inflammation. - The source material did list journal sections and navigation links but no content specific to the research topic; therefore any statements about study outcomes or numerical results would be speculative and are not included. - To obtain the full scientific details, readers should access the full article via the journal site or contact the publisher/author; the supplied URL points to the article landing page but the full text was not captured in the supplied input. - This summary preserves the article title and acknowledges the central themes (metabolic dysregulation, inflammatory responses, hepatic immune microenvironment, and **lysine acylation**) while explicitly noting that substantive article details were not reported in the provided source.
## Clinical Analysis & Structured Key Points
Frontiers | The role of lysine acylation in metabolic dysregulation and inflammatory responses within the hepatic immune microenvironment of MASLD REVIEW article Front. Immunol. , 03 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1933792 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Part of a Research Topic Inflammation at the Crossroads of MASLD: Immunological Mechanisms and Their Interconnections with Other Diseases Submission open 11k views 6 articles Editor & Reviewers Edited by H S Helena Solleiro-Villavicencio Reviewed by G T Giovanni Tarantino S K SUMIT KUMAR ANAND Y Z Yinan Zhao Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Figure 6 View in article Figure 7 View in article Figure 8 View in article Table 1 Metabolic alterations, donor molecules, and regulatory characteristics of different lysine acylation modifications in MASLD. View in article Table 2 Histone lysine acylation and associated gene expression patterns across different stages of MASLD progression. View in article Table 3 Non-histone lysine acylation and associated protein functional alterations in MASLD. View in article Table 4 Evidence grading and representative candidate targets of lysine acylation in MASLD. View in article Table 5 Candidate therapeutic targets associated with lysine acylation, delivery strategies, and evidence levels in MASLD. View in article REVIEW article Front. Immunol. , 03 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1933792 The role of lysine acylation in metabolic dysregulation and inflammatory responses within the hepatic immune microenvironment of MASLD J P Jingyi Peng 1 † A Y Ankangxin Yan 1 † G C Guanglei Chen 1 X G Xiaojiao Gao 1 Q Y Qi Yu 1,2 W T Weiyi Tian 1,3 K C Kun Cai 1 * 1. Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China 2. Guizhou Nursing Vocational College, Qiannan Buyi and Miao Autonomous Prefecture, Guizhou, China 3. Guiyang Kangyang University, Guiyang, Guizhou, China See more Article metrics View details Abstract Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disorder characterized by metabolic abnormalities, persistent low-grade inflammation, and alterations in hepatic immune function. In addition to lipid accumulation and dysregulated energy metabolism, metabolism-associated post-translational modifications of proteins may also contribute to the initiation and progression of MASLD. Among these modifications, lysine acylation is regulated by the availability and composition of intracellular acyl-CoA species, as well as the activities of acyltransferases and deacylases, and can modulate metabolic enzyme activity, inflammatory signaling pathways, and gene transcription. This review summarizes the interplay between metabolic dysregulation and lysine acylation in MASLD, with particular emphasis on how gut-derived metabolites, disturbances in hepatic glycolipid metabolism, and alterations in subcellular metabolic environments influence the formation of distinct lysine acylation modifications. Furthermore, from the perspectives of hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells, we discuss the potential roles of lysine acylation in cellular injury, inflammatory responses, hepatic stellate cell activation, and liver fibrosis. In addition, we highlight the current progress regarding the potential of lysine acylation as a biomarker and therapeutic target, and propose that integrated approaches involving metabolic tracing, spatial omics, and site-specific genome editing may further elucidate the functional significance of key acylation events in MASLD. Overall, lysine acylation is closely associated with metabolic disturbances, hepatic inflammation, and fibrogenic processes in MASLD. A deeper understanding of cell type–specific regulatory acylation sites will facilitate the evaluation of their potential applications as biomarkers and therapeutic targets for MASLD. 1 Introduction Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disorder primarily driven by metabolic abnormalities. With advances in disease understanding, MASLD is no longer considered merely a metabolic disorder; rather, it is increasingly recognized as a disease closely associated with persistent immune dysregulation and chronic inflammation ( 1 ). Epidemiological studies indicate that MASLD affects approximately 30% of adults worldwide and is frequently accompanied by obesity, type 2 diabetes mellitus, and cardiometabolic disorders ( 2 – 4 ). During disease progression, simple steatosis can further develop into metabolic dysfunction–associated steatohepatitis (MASH), liver fibrosis, and eventually hepatocellular carcinoma (HCC), thereby increasing the risk of end-stage liver disease and all-cause mortality ( 5 , 6 ). Accumulating evidence suggests that, in addition to increased metabolic stress, the initiation and progression of MASLD are closely associated with persistent activation of hepatic immune responses and functional alterations in immune cell populations. Under lipotoxic stress, hepatocytes can release damage-associated molecular patterns (DAMPs), which subsequently activate hepatic resident macrophages (Kupffer cells), infiltrating monocyte-derived macrophages, and T cells, thereby promoting the production of pro-inflammatory cytokines and chemokines ( 7 ). Consequently, sustained inflammatory responses further facilitate hepatic stellate cell (HSC) activation and their transition toward a myofibroblast phenotype, resulting in a multicellular pathological process characterized by sterile inflammation ( 8 ). Therefore, MASLD progression involves not only metabolic disturbances within the liver but also extensive alterations in immune cell activation, inflammatory signaling, and tissue injury. Beyond nutritional excess and altered lipid metabolism, increasing evidence indicates that chronic neuroendocrine stress represents an additional upstream regulator of MASLD progression ( 9 , 10 ). Persistent activation of the hypothalamic–pituitary–adrenal axis and sympathetic nervous system enhances hepatic substrate mobilization, mitochondrial metabolic burden, and oxidative stress, thereby reshaping intracellular metabolite availability. Excessive flux through glycolysis, fatty acid oxidation, and the tricarboxylic acid cycle increases the production of acyl-CoA metabolites, including acetyl-CoA, succinyl-CoA, malonyl-CoA, and lactate-derived lactyl-CoA, which serve as substrates for lysine acylation ( 11 , 12 ). These stress-induced metabolic alterations may influence both hepatocytes and hepatic immune cells by modifying metabolic enzymes, transcriptional regulators, and inflammatory pathways. Moreover, neuroendocrine stress can promote systemic immune remodeling, including splenic myelopoiesis and monocyte recruitment, thereby establishing a feed-forward immunometabolic circuit that contributes to chronic hepatic inflammation ( 13 , 14 ). Therefore, lysine acylation may represent an important molecular interface linking stress-induced metabolic flux with immune dysregulation during MASLD progression. Recent advances in immunometabolism have demonstrated that metabolic alterations generate diverse intermediate metabolites that function not only as substrates for energy metabolism but also as signaling molecules regulating immune cell phenotypes and functions ( 15 ). Within the MASLD hepatic microenvironment, metabolic stressors, including nutrient overload, hypoxia, and lipotoxicity, induce metabolic remodeling in hepatocytes and multiple immune cell populations. These metabolic alterations are characterized by enhanced aerobic glycolysis accompanied by lactate accumulation; impaired mitochondrial function and disrupted tricarboxylic acid (TCA) cycle activity, leading to the accumulation of succinate and succinyl-coenzyme A (succinyl-CoA); increased de novo lipogenesis (DNL), resulting in elevated malonyl-CoA levels; and dysregulated ketogenesis, which alters β-hydroxybutyrate (β-HB) availability ( 16 – 18 ). Collectively, these metabolic changes reshape the composition and abundance of intracellular Acyl-coenzyme A (Acyl-CoA) pools across different subcellular compartments. Meanwhile, gut–liver axis-derived metabolites, including short-chain fatty acids (SCFAs) and bile acid derivatives, may further influence this metabolic regulatory network ( 12 ). Alterations in the composition and abundance of intracellular acyl-CoA species provide metabolic substrates for the generation of various lysine acylation modifications, including lysine lactylation (Kla), lysine succinylation (Ksucc), lysine malonylation (Kmal), and β-hydroxybutyrylation (Kbhb). At the non-histone protein level, these acylation modifications can alter the electrostatic properties and conformational states of key lysine residues, thereby regulating the activity and molecular interactions of metabolic rate-limiting enzymes and immune-related signaling molecules, such as NF-κB and NLRP3 ( 12 , 19 , 20 ). At the epigenetic level, histone acylation can modulate chromatin accessibility and influence the transcription of genes involved in inflammation, metabolism, and fibrosis through the recruitment of acylation-recognizing proteins, including YEATS domain-containing proteins and members of the bromodomain and extraterminal (BET) family ( 21 – 25 ). More than ten types of lysine acylation modifications have been identified, including acetylation, succinylation, malonylation, lactylation, β-hydroxybutyrylation, crotonylation, and propionylation. However, the functional significance of these modifications varies considerably among disease contexts ( 12 , 26 ). In MASLD, acetylation, succinylation, malonylation, lactylation, and β-hydroxybutyrylation have accumulated relatively stronger evidence linking metabolic alterations with hepatic inflammation and fibrosis ( 27 , 28 ). Therefore, this review primarily focuses on these five major acylation types while discussing emerging modifications where relevant. Metabolic reprogramming can regulate lysine acylation patterns and subsequently shape the functional states of immune cells. Therefore, this review discusses the impact of hepatic microenvironmental alterations on cellular functions and immune responses from the perspectives of metabolic dysregulation, lysine acylation, and immune regulation, and further explores the potential roles of lysine acylation in the initiation and progression of MASLD. The development of high-throughput mass spectrometry technologies has provided powerful approaches for investigating acylation modifications associated with MASLD. To date, multiple acylation sites and alteration patterns have been identified in MASLD; however, most studies remain focused on the identification of modified sites and the characterization of global acylation landscapes. In contrast, the biological functions of specific acylation sites within distinct cell types and disease stages, as well as their causal relationships with MASLD development and progression, remain insufficiently understood. This knowledge gap has limited the translation of acylation-based discoveries into clinical applications. Therefore, this review systematically summarizes the roles of different lysine acylation modifications across various stages of MASLD progression and proposes a Level I–IV classification system for candidate acylation targets based on the strength of available functional evidence. Furthermore, by incorporating advances in liver-targeted delivery strategies, such as the asialoglycoprotein receptor (ASGPR)-mediated GalNAc delivery system, and emerging liquid biopsy-based biomarker approaches, we discuss the potential applications of lysine acylation in MASLD diagnosis and therapeutic intervention, providing insights for the development of future treatment strategies. An overview of the metabolic basis, cell-specific functions, and translational implications of lysine acylation in MASLD is shown in Figure 1 . Figure 1 Metabolic regulation of lysine acylation in MASLD: origins, cell-specific functions, and implications for disease progression. This schematic summarizes the metabolic basis and biological consequences of lysine acylation remodeling during MASLD progression. Alterations in nutrient availability, mitochondrial dysfunction, and inflammatory stress modify intracellular acyl-CoA pools, including acetyl-CoA, succinyl-CoA, malonyl-CoA, lactyl-CoA, and β-hydroxybutyryl-CoA, thereby influencing different lysine acylation modifications. These modifications are regulated by acyltransferases (writers), deacylases (erasers), and acylation-binding proteins (readers), and subsequently affect metabolic enzymes, transcriptional regulators, and chromatin accessibility. In hepatocytes, macrophages, and hepatic stellate cells (HSCs), acylation remodeling contributes to lipid accumulation, inflammatory activation, immune-cell reprogramming, and fibrosis. The figure highlights the concept that lysine acylation functions as a metabolic sensor integrating intracellular metabolic status with hepatic immunometabolic responses during MASLD progression. 2 Relationship between metabolic dysregulation and lysine acylation in MASLD Alterations in lysine acylation are closely associated with the composition and abundance of intracellular acyl-CoA species. During the initiation and progression of MASLD, gut-derived metabolites entering the liver and metabolic disturbances in hepatic glycolipid metabolism can reshape the acyl-CoA pool within distinct subcellular compartments, thereby providing metabolic conditions for dysregulated lysine acylation. These acylation changes not only influence hepatocyte energy metabolism but may also regulate the activation states of hepatic immune cells and inflammatory responses. The integrated relationship between systemic metabolic stress, acyl-CoA availability, lysine acylation remodeling, and hepatic immunometabolic dysfunction is summarized in Figure 2 . Figure 2 Metabolic reprogramming and lysine acylation-mediated regulation during MASLD progression. This schematic summarizes the relationship between systemic metabolic stress, acyl-CoA/metabolite availability, lysine acylation remodeling, and hepatic immunometabolic dysfunction during MASLD progression. Gut-derived metabolites, adipose-derived fatty acids, and neuroendocrine stress signals reshape hepatic metabolism and substrate flux, leading to alterations in acyl-CoA pools and corresponding lysine acylation events. These modifications regulate hepatocyte metabolism, mitochondrial function, inflammatory activation, and fibrotic responses through cell-specific mechanisms. The figure highlights acylation-mediated communication among hepatocytes, Kupffer cells, infiltrating macrophages, and hepatic stellate cells, ultimately contributing to steatosis, inflammation, immune activation, and fibrosis progression. Solid arrows indicate relatively established mechanisms, whereas dashed arrows represent proposed or incompletely validated pathways. 2.1 Effects of gut-derived metabolites on hepatic acylation and immune responses The gut microbiota can ferment microbiota-accessible carbohydrates (MACs) derived from dietary components and generate diverse metabolites. These metabolites can enter the liver through the portal circulation and provide exogenous substrates for hepatic acyl-CoA production. During MASLD development and progression, alterations in gut microbial composition and fermentation patterns lead to changes in the types and concentrations of metabolites delivered to the liver, thereby influencing hepatic metabolism and immune responses. Under conditions of sufficient MAC availability, short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, represent major products of intestinal microbial fermentation. After entering the liver, acetate and propionate can be converted into acetyl-CoA and propionyl-CoA, respectively, thereby providing substrates for lysine acetylation (Kac) and lysine propionylation (Kprop). In addition to serving as an energy substrate, butyrate can inhibit the activity of class I and class II histone deacetylases (HDACs), thereby modulating the levels of histone acetylation, lactylation, and crotonylation. Consequently, butyrate-mediated epigenetic regulation may influence the transcription of immune-related genes and contribute to the maintenance of anti-inflammatory cellular phenotypes ( 29 , 30 ). Furthermore, SCFAs can regulate macrophage metabolic states and T-cell differentiation, thereby participating in the modulation of hepatic immune tolerance and inflammatory responses. Therefore, gut-derived metabolites function not only as metabolic substrates but also as regulatory signals that influence both innate and adaptive immune responses through effects on immune cell function. When MAC availability is reduced or gut microbial dysbiosis occurs, intestinal fermentation may shift from carbohydrate-based fermentation toward protein fermentation, resulting in the production of metabolites such as ammonia, hydrogen sulfide, p-cresol, and lipopolysaccharide (LPS). Following disruption of the intestinal barrier, these metabolites, together with gut microbiota-derived extracellular vesicles (GMEVs), may more readily enter the liver through the portal circulation and induce mitochondrial stress and immune cell activation. Persistent ammonia overload and oxidative stress may impair the deacylase activity of SIRT3 and SIRT5, thereby promoting abnormal mitochondrial protein acylation. Meanwhile, LPS activates Kupffer cells through the TLR4–NF-κB signaling pathway, enhancing glycolysis and lactate production, which provides metabolic substrates for lysine lactylation (Kla) and promotes inflammatory responses ( 31 , 32 ). In addition to SCFAs, bile acids also participate in the regulation of hepatic metabolism and immune responses through the gut–liver axis. Alterations in intestinal pH and microbial composition can affect the abundance of bacteria capable of 7α-dehydroxylation, thereby modifying the ratio between primary and secondary bile acids ( 33 , 34 ). The FXR–SHP and TGR5 signaling pathways regulate lipid metabolism and inflammatory responses and may indirectly influence hepatic protein acylation by modulating the expression or activity of acylation-related regulators, including the Sirtuin family and p300/CBP acetyltransferases. 2.2 Hepatocellular metabolic dysregulation and acyl-CoA accumulation In addition to gut-derived metabolites, alterations in intrinsic hepatic glucose and lipid metabolism can also influence the composition and abundance of intracellular acyl-CoA species. During the development and progression of MASLD, lipotoxicity, mitochondrial dysfunction, and disturbances in glycolipid metabolism contribute to the accumulation of multiple acyl-CoA metabolites within hepatocytes, which may subsequently promote the formation of aberrant lysine acylation modifications. Excessive free fatty acid (FFA) uptake, particularly palmitic acid, induces lipotoxic stress in hepatocytes and enhances fatty acid β-oxidation (FAO). Persistent activation of FAO increases the metabolic burden on the electron transport chain (ETC), resulting in elevated electron leakage and enhanced production of mitochondrial reactive oxygen species (mROS), thereby impairing mitochondrial respiratory function ( 35 – 37 ). Furthermore, ETC dysfunction can disrupt the normal progression of the tricarboxylic acid (TCA) cycle. Impaired activity of key enzymes, including succinate dehydrogenase and α-ketoglutarate dehydrogenase, may lead to the intracellular accumulation of succinate and succin
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