Post-translational modifications (PTMs) encompass a
diverse range of chemical alterations that occur at the side chains
or terminal ends of proteins following translation. According to
data from the SWISS-PROT database, the five most prevalent PTMs are
phosphorylation, acetylation, glycosylation, amidation and
hydroxylation (1). These
modifications play critical roles in the regulation of protein
function, stability and interactions with other biomolecules. In
eukaryotic cells, chromosomes consist of highly compacted DNA and
proteins, and PTMs are indispensable for altering chromatin
structure and function.
In 1964, Vincent Allfrey first identified protein
acetylation in the calf thymus nucleus in vitro and
established the foundation for subsequent research on this
modification (2). Lysine
acetylation is a reversible PTM that profoundly influences diverse
cellular processes, including chromatin remodeling, transcriptional
regulation, DNA damage repair, cellular metabolism, cytoskeletal
organization and apoptosis (3).
Lysine acetylation is primarily controlled by two
key enzyme families: Lysine acetyltransferases (KATs) and lysine
deacetylases (KDACs) (4). KATs
facilitate the addition of acetyl groups from acetyl-CoA to lysine
residues, while KDACs catalyze the removal of these groups, thereby
sustaining the dynamic equilibrium between acetylation and
deacetylation.
Histones are the most frequently acetylated
proteins. They serve as fundamental units for DNA organization,
functioning as the structural core of chromatin. Canonical histones
are modified by various KATs and KDACs (5). The acetylation of histone lysine
residues neutralizes their positive charges, which weakens
electrostatic attractions among nucleosomes, loosens chromatin
structure, and consequently facilitates gene transcription
(6). Proteomics analyses have
demonstrated that numerous non-histone proteins can also be
acetylated. These acetylated non-histone proteins participate in a
wide range of metabolic regulation, RNA maturation, translational
control, protein folding, chromatin remodeling, proteolysis and the
maintenance of cytoskeletal architecture (7).
Lysine acetylation modulates protein function
through altering protein stability, catalytic activity and
intracellular distribution, as well as interacting with other PTMs.
Moreover, this modification regulates both protein-protein and DNA
protein interactions. As a flexible regulatory mechanism, lysine
acetylation provides cells with a refined control over
physiological processes and offers novel insights into disease
pathogenesis. Recently, enzymes involved in acetylation have
emerged as promising targets for drug development.
Protein acetylation was first identified in nuclear
histones in the 1960s and was initially regarded as a regulatory
mechanism predominantly involved in chromatin organization and gene
transcription. Accordingly, early studies referred to this
modification as 'histone acetylation' (8). With the advent of proteomics and
mass spectrometry in the early 21st century, it has become clear
that acetylation is not restricted to histones, but is also
widespread among numerous non-histone proteins in the cytoplasm and
mitochondria. Consequently, the concept has been broadened and is
now more accurately described as 'lysine acetylation', which is
increasingly recognized as a pivotal regulator of diverse
biological processes (9). Mass
spectrometry remains the primary tool for the site-specific
identification and quantitative analysis of protein acetylation.
More recently, the Iseq-Kac (internal standard-assisted
quantification) strategy has been introduced, allowing the
efficient profiling of the acetylome under low-abundance conditions
without enrichment procedures (10) (Fig. 1).
Based on their subcellular localization, KATs can be
broadly classified into two major categories: Type A and Type B.
Type A KATs are mainly localized in the nucleus and regulate
chromatin accessibility, transcriptional activation and chromatin
remodeling by catalyzing histone acetylation. Representative
members include CBP and p300. By contrast, Type B KATs are
predominantly cytoplasmic and are involved in the acetylation of
newly synthesized histones and non-histone proteins, thereby
playing essential roles in protein maturation, nuclear transport,
and post-transcriptional regulation. In addition to their distinct
subcellular localization, KATs exhibit specific substrate
preferences. For example, GCN5 preferentially catalyzes histone
H3K14 acetylation, while exhibiting relatively limited activity
toward global nucleosome acetylation (11).
Furthermore, based on sequence homology and the
characteristics of catalytic domains, eukaryotic KATs are mainly
classified into several families, including the GCN5-related
N-acetyltransferase (GNAT), CBP/p300, MYST, basal transcription
factor, NCoA and other families. The GNAT family mainly consists of
GCN5, PCAF and their associated transcriptional coactivator
complexes such as SAGA, ATAC and TFTC, and has been implicated in
cancer, cardiovascular disorders, inflammatory diseases and genetic
disorders (12-19). The CBP/p300 family primarily
functions as transcriptional coactivators with intrinsic
acetyltransferase activity and plays critical roles in gene
regulation, cellular differentiation and disease development,
including cancer and developmental disorders (20-23). The MYST family comprises TIP60,
MOZ, MORF and HBO1, as well as multiple associated protein
complexes, including NuA4, MSL, NSL and SWR1-like complexes.
Members of this family participate in the immune responses, and
their dysregulation has been shown to be associated with various
pathological conditions, particularly inflammation and malignancies
(24-30). In addition, KATs associated with
basal transcription factors and nuclear receptor coactivators, such
as TFIID, TFIIIC and NCoA complexes, contribute to transcriptional
regulation and have been linked to human diseases (31-33). Other KAT-associated complexes,
such as the HAT1-containing HAT-B complex and HAT4, have also been
implicated in specific pathological conditions, although their
biological functions and disease associations remain less
extensively characterized (34-36). The classification of KAT
families, associated complexes and their disease relevance are
summarized in Table I.
KDACs function together with KATs to maintain
acetylation homeostasis. Based on their catalytic mechanisms, KDACs
can be classified into Zn2+-dependent histone
deacetylases (HDACs) and NAD+-dependent sirtuins
(37).
Class II HDACs consist of two subclasses: Class IIa
(HDAC4, HDAC5, HDAC7, and HDAC9) and Class IIb (HDAC6 and HDAC10).
These enzymes exhibit dynamic shuttling between the nucleus and
cytoplasm (53-55). Among them, HDAC6 mainly targets
non-histone substrates, such as tubulin, and plays important roles
in regulating cell migration and stress responses (56-58). Abnormalities in Class II HDAC
function have been implicated in inflammatory disorders, metabolic
dysfunction, neurological injury and cancer (59-69).
Class III HDACs, also known as the sirtuin family
(SIRT1-SIRT7), play essential regulatory roles in multiple
diseases, regulate metabolism, stress responses, mitochondrial
function and aging processes, and are involved in diverse diseases,
including cancer, cardiovascular disorders and metabolic diseases
(70-88). Class IV HDACs mainly consist of
HDAC11, which has been reported to participate in immune regulation
and pathological processes (89,90). The classification of the
different KDAC families and their associated diseases are
summarized in Table II.
Lysine acetyltransferases and deacetylases play
essential roles in cellular physiology. Their interplay modulates
the acetylation status of lysine residues, thereby regulating
chromatin dynamics and influencing gene expression, cellular
metabolism, and other biological processes.
Lysine acetylation plays a crucial role in
regulating gene transcription by modulating chromatin structure,
transcription factor activity and the assembly of transcriptional
regulatory complexes.
Ada3 is acetylated at lysine residues, together with
its interaction with GCN5 and SPT7, promotes the formation of SAGA
homodimers. This complex exhibits a high nucleosome acetylation
efficiency, thereby enhancing its transcriptional activity. The
findings underscore the essential contribution of acetylation to
transcriptional regulation and the central role of the SAGA complex
in gene expression (91). The
expression of CCND1 results from the HDAC8-mediated deacetylation
of PKM2, which subsequently affects its interaction with β-catenin
(92). Additionally, the
KAT5-mediated N-terminal acetylation of cGAS promotes the
transcription of antiviral genes as part of the innate immune
response (93). HDAC3 activity
has been shown to initiate the transcription of the Ucp1 gene and
enhance the expression of genes involved in mitochondrial oxidative
phosphorylation, which are essential for thermogenesis in brown
adipose tissue (94).
PCAF-mediated acetylation of METTL3 at K177 disrupts its
interaction with translation initiation factor subunit EIF3H,
thereby reducing ribosomal translation efficiency (95). The acetylation of histone3 at K56
functions as a genome-wide transcriptional activator by enhancing
promoter-proximal nucleosome destabilization and reassembly during
the S-phase (96). Additionally,
transcription assays using RNAP-II have revealed that nucleosomes
bearing N-terminally acetylated H3 significantly reduced RNAP-II
pause, resulting in increased transcript abundance (97).
In response to DNA damage, lysine acetylation
regulates genome stability by modulating chromatin remodeling,
facilitating the recruitment of DNA repair factors, and
coordinating DNA repair pathway activation.
The acetylation of TDP-43 at K136 affects RNA
binding and splicing, inducing phase separation and the
accumulation of insoluble aggregates composed of TDP-43 that is
pathologically phosphorylated and ubiquitinated (98). The acetylation and
autophosphorylation of TIP60 initiate DNA damage responses by
activating ataxia-telangiectasia mutated (ATM), while SIRT7
facilitates DNA repair by binding to and removing acetyl groups
from ATM (99). The acetylation
of nuclear lamin B1 (LMNB1) at K134 modulates nuclear peripheral
stability, cell cycle progression, and DNA repair, in part by
impairing 53BP1 recruitment to DNA lesions, thereby inhibiting
non-homologous end joining and delaying the G1/S transition
(100). In response to
poly-ADP-ribosylation, pyruvate dehydrogenase E1α is rapidly
localized to chromatin, where it produces acetyl-CoA at sites of
DNA double-strand breaks, promoting chromatin relaxation and
facilitating repair factor recruitment and genome stability
(101). Upon DNA damage,
acetylation of E2F1 generates a specific recognition motif for the
bromodomains of KAT3A and KAT3B, facilitating their recruitment to
sites of double-strand breaks. This localization promotes further
acetylation processes and the assembly of chromatin-remodeling and
DNA repair complexes, including Tip60, BRG1 and NBS1 (102).
The process of autophagy is fundamental to the
maintenance of intracellular equilibrium, particularly during
nutrient deprivation, by degrading stored energy sources.
Acetyl-CoA, a primary intracellular acetyl donor, promotes mTORC1
activation by enhancing ep300-mediated acetylation of raptor at
K1097, thereby inhibiting autophagy (103,104).
GCN5-mediated acetylation inhibits TFEB
transcriptional activity by preventing its dimerization, owing to a
non-conserved K116 site within the MiT/TFE family, thereby
impairing autophagosome formation (105). SIRT1-deficient embryos and
neonatal mice accumulate mitochondria, and exhibit elevated p62
levels, AMPK activation and lethality. NAD+, essential
for cellular processes and a cofactor for some histone
deacetylases, is critical for autophagy regulation, particularly
under starvation conditions where SIRT1 activity is
NAD+-dependent (106). NAMPT expression is regulated by
the acetylation of upstream enhancers and modulates intracellular
NAD+ levels (107).
The acetylation also affects metabolism-related gene expression,
and metabolic states reciprocally influence acetyltransferase and
deacetylase activities. KAT8 is crucial for metabolic regulation,
and MOF depletion during neuronal development is associated with
the accumulation of stearic acid and long-chain fatty acids
(108). NatB-mediated
N-terminal acetylation of Act1 promotes actin filament assembly,
aiding Atg9 vesicle trafficking and autophagosome formation.
Acetylation of the N-terminus of Vps1 enhances its interaction with
SNARE proteins, facilitating autophagosome-vacuole fusion (109). RB1CC1/FIP200, a key autophagy
regulator, is acetylated at K276 by CREB, which reduces its
ubiquitination and degradation, thereby enhancing autophagic
activity in diseases, such as breast cancer (110).
Lysine acetylation is also a key factor involved in
the dynamic changes in chromatin organization and transcriptional
regulation. Thus, lysine acetylation plays an essential role in
maintaining pluripotency and directing cellular differentiation by
modulating gene expression programs.
KAT5 is essential for embryonic stem cell
development, and its deficiency impairs embryogenesis (111). The proper regulation of KAT
enzymatic function is crucial for sustaining equilibrium between
hematopoietic stem cell self-renewal and lineage commitment. MOF
deficiency impairs erythroid development, likely due to reduced
H4K16ac levels and altered chromatin accessibility (112). Acetyl-CoA influences endodermal
differentiation by promoting the acetylation of Smad3 at lysine 19,
a key transcription factor in endodermal lineage commitment
(113). KAT7 regulates adult
HSCs, and its deletion causes HSC quiescence, hematopoietic
failure, and pancytopenia in mice (114). Histone deacetylase SIRT6
interacts with Pol II to inhibit NELF release and, maintain Pol II
pausing. SIRT6 deficiency or chromatin defects enrich H3K9ac and
H3K56ac under glucose starvation, activating CDK9 phosphorylation
of NELF and Pol II and recruiting MYC, BRD4, PAF1, AFF4 and ELL2,
which enhances transcriptional regulation of genes that participate
in metabolism, protein synthesis and development (115).
Cell cycle progression requires dynamic regulation
of chromatin structure and gene expression. Lysine acetylation
contributes to this process by controlling histone modification
patterns and regulating the activity of cell cycle-associated
proteins. KATs and KDACs function differently during interphase and
mitosis. KAT5 acetylates multiple lysine residues on H2A, H3 and H4
during interphase. During mitosis, KAT5 acetylates Aurora-B at
residue K215, preventing its dephosphorylation by PP2A and ensuring
an accurate metaphase-to-anaphase transition (116). KAT5 deficiency disrupts
metaphase alignment and inhibits cell growth during mitosis
(117). The inhibition of the
CBP bromodomain by CCS1477 results in cell cycle arrest and
enhances differentiation in a range of tumor (118). Tip60 reverses HDAC8-mediated
deacetylation at K202, limiting HDAC8 activity, enhancing SMC3
acetylation, impairing cohesion and cell cycle progression, and
inducing G2/M arrest (119).
Aberrant CHK2 activation induces cell cycle inhibition and
subsequent cell death, while SIRT1 directly engages CHK2 to mediate
its deacetylation at the K520 site, thereby reducing CHK2
phosphorylation, dimerization, and activation, and maintaining
genome integrity and homeostasis (120). Taken together, these findings
highlight lysine acetylation as a dynamic epigenetic regulatory
layer that integrates transcriptional regulation, genome
maintenance, metabolism, cell fate determination and cell cycle
progression (Fig. 2).
Lysine acetylation does not function independently,
but interacts extensively with other PTMs, including
ubiquitination, phosphorylation, methylation and lactylation. These
interactions regulate protein stability, activity and cellular
signaling. Acetylation protects proteins from ubiquitination by
masking lysine residues, thereby preventing their degradation. For
example, HDAC inhibitors, such as TSA, enhance ENaC acetylation and
abundance, while reducing its ubiquitination. By contrast, HDAC7
promotes ENaC ubiquitination (121). Conversely, acetylation enhances
protein ubiquitination and degradation. PEPCK1 acetylation recruits
the E3 ligase UBR5, which leads to its degradation (122). AMPK phosphorylates ASPP2 in
response to irradiation (IR), promoting apoptosis. BRD4 inhibition
by JQ-1 disrupts histone acetylation and sensitizes AMPK-deficient
cells to IR (123). PGAM5
mediates ME1 dephosphorylation at S336 and promotes ACAT1 at
residue K337 acetylation (124). COP1, an E3 ligase and tumor
suppressor, enhances JNK phosphorylation and c-Jun nuclear
translocation and inhibits HDAC3 expression (125). The acetylation of LHPP inhibits
GSK3B phosphorylation, and modulates HIF1A-driven glycolysis and
metastasis in gastric cancer (126). N-terminal acetyltransferase
modulates H3K4 methylation by blocking Set1-COMPASS acetylation via
Shg1 proline mutation (127).
The MOF-mediated acetylation of UHRF1 at K670 reduced its
recruitment of DNMT1 during replication, thereby lowering DNA
methylation (128). KAT8
acetylates ALKBH5 at residue K235, enhancing its m6A demethylation
activity (129). The
acetylation of the H3 tail facilitates access to other H3K4 methyl
readers (130). SIRT3
downregulation increased PDHA1 acetylation in renal tubular
epithelial cells, leading to lactate overproduction and Fis1 K20
lactylation, thereby promoting mitochondrial fission, ATP
depletion, mtROS generation and apoptosis (131). RBM25 interacts with Acly,
mediating exon 14 skipping to generate the acly isoform, which
promotes K918/995 lactylation and glycolysis-driven acetyl-CoA
production by pro-inflammatory macrophages (132) (Fig. 3).
Lysine acetylation plays a pivotal role in the
pathogenesis of diseases. In cancer, acetylation or deacetylation
tightly regulate gene transcription and host immune response.
Acetylation can exert an inhibitory effect on tumor progression and
promote differentiation by modulating the expression of
cancer-related genes (133). It
also enhances the infiltration and cytotoxicity of innate immune
cells, such as T-cells, while reducing the immunosuppressive
function of Tregs, ultimately leading to cancer cell clearance. In
cardiovascular diseases, the dysregulation of lysine acetylation
has been linked to the onset and progression of hypertension,
atherosclerosis, myocardial infarction and cardiac hypertrophy
(134-137). The modulation of lysine
acetylation also reduces ameliorates pulmonary damage in
inflammation-induced lung injury (138) (Fig. 4).
Acetylation and deacetylation exert profound effects
on cancer initiation and progression. Programmed death-ligand 1
(PD-L1) is commonly found to be highly expressed across some solid
malignancies, such as melanoma, non-small cell lung cancer and
breast carcinoma. Increasing evidence suggests that the inhibition
or downregulation of PD-L1 expression represents a valuable and
promising therapeutic approach for the treatment of these types of
cancer (139). Programmed cell
death protein 1 (PD-1) signaling enhances PD-L1 expression and
reduces the apoptotic susceptibility of tumor cells. Furthermore,
multiple clinical studies have demonstrated that HDAC2 is
significantly overexpressed in tumor tissues from patients with
various malignancies, including colorectal, gastric and breast
cancer. Elevated HDAC2 expression levels are closely associated
with a reduced overall survival (OS), a poor prognosis and advanced
tumor stages, indicating its potential clinical value as a
diagnostic and prognostic biomarker (140). Mechanistically, the deacetylase
HDAC2 in mice has been shown to interacts with PD-L1 and reduces
its acetylation level (141).
In addition, HAT1 expression is increased in clinical pancreatic
cancer samples, and its high expression is closely associated with
a poor prognosis of patients with pancreatic cancer, suggesting the
clinical relevance of HAT1 in pancreatic tumor tissues (142). Further research has revealed
that HAT1 acetylates PD-L1 at H4 at K5 and K12, promoting BRD4
recruitment and increasing PD-L1 transcription in pancreatic
cancer. HAT1 knockdown enhances the infiltration of
CD45+ CD4+ and CD45+ and
CD8+ T-cells, suppresses CD11b+
Gr1+ myeloid infiltration, and reduces tumor growth and
metastasis by downregulating PD-L1 (142). These findings indicate that
acetylation regulation directly controls tumor cell intrinsic
signaling and shapes the tumor immune microenvironment by
modulating of immune checkpoint expression.
A prospective clinical study found that patients
with CBP mutations had a significantly reduced OS, progression-free
survival and event-free survival, suggesting that CBP mutations are
an independent predictor of a poor prognosis in cancer (143). Further investigations
demonstrated that the CBP-mediated acetylation of MOB1 at K11
activates LATS1, which in turn stimulates the Hippo signaling
cascade, restricts YAP/TAZ nuclear localization, and suppresses
tumorigenesis (144).
Similarly, the acetylation of RRM2 by KAT7 at K95 disrupts its
dimerization, functioning as a molecular switch to inhibit dNTP
synthesis, stall DNA replication forks, and suppress tumor cell
proliferation (145). Finally,
WEE1 is a potential target for cancer therapy; SIRT1 interacts with
and deacetylates WEE1 to maintain its inactive state (146). This pathway opens new avenues
for anticancer strategies by elucidating the complex
acetylation/deacetylation regulation in the tumor
microenvironment.
In hypertension research, the inhibition of HDACs
has proven to be effective in preventing hypertension. In
spontaneously hypertensive models, the HDAC inhibitor, valproic
acid, reduces inflammatory responses, myocardial hypertrophy and
oxidative stress indicators (147). Clinical studies have
demonstrated that the acetylation level of the mitochondrial
protein cyclophilin D is markedly increased (by ~280%) in small
arterial tissues from patients with hypertension. This alteration
is accompanied by the decreased expression of SIRT3 and increased
GCN5L1 levels, suggesting that dysregulated mitochondrial protein
acetylation may contribute to hypertension-associated endothelial
dysfunction (148). Mechanistic
analyses have revealed that SIRT3 protects against angiotensin
II-induced hypertension by promoting mitophagy and clearing damaged
mitochondria, thereby reducing production of reactive oxygen
species (149). This mechanism
alleviates vascular injury and myocardial fibrosis, and improves
hypertensive cardiovascular pathology.
In the context of heart failure and pathological
cardiac hypertrophy, the acetyltransferase p300 plays a key
regulatory role. Clinical sample analyses have demonstrated that,
compared with normal cardiac tissues, p300 expression is
significantly increased in left ventricular tissues from patients
with ischemic cardiomyopathy, dilated cardiomyopathy and end-stage
heart failure, suggesting that p300 may contribute to pathological
cardiac remodeling (150). p300
functions as a coactivator of cardiac hypertrophic transcription
factors (151). p300 directly
acetylates GATA4, boosting hypertrophic gene expression during
cardiac remodeling (152). p300
also enhances MEF2 transcriptional activity via acetylation,
further promoting hypertrophy. SIRT1 deacetylates p300, attenuates
acetyltransferase activity, and delays cardiac hypertrophy. SIRT1
knockout mice exhibit increased MEF2 acetylation and dilated
cardiomyopathy, underscoring the protective role of SIRT1 (153). In heart failure, the reduced
expression and activity of SERCA2a are hallmarks. The p300-mediated
acetylation of SERCA2a at K492 impairs its function, whereas SIRT1
restores SERCA2a levels and cardiac function (154). Taken together, these findings
reveal that dysregulated acetylation homeostasis contributes to the
progression of cardiovascular disease by affecting mitochondrial
function, inflammatory responses and cardiac remodeling, suggesting
acetylation regulators as potential therapeutic targets.
Recent evidence has demonstrated that
acetylation-regulating enzymes not only influence the transcription
of inflammation-related genes, but also contribute to disease
progression by modulating immune cell functions, oxidative stress
responses and tissue fibrotic processes.
In chronic obstructive pulmonary disease (COPD),
HDAC3 has been suggested to function as a key regulator of
glucocorticoid [inhaled corticosteroid (ICS)] treatment
responsiveness. Recent clinical research has revealed that HDAC3
expression is elevated in airway smooth muscle cells from patients
with COPD who are unresponsive to ICS therapy, whereas patients who
respond to ICS treatment exhibit relatively lower HDAC3 levels.
These findings suggest that the dysregulated expression of HDAC3
may influence glucocorticoid-mediated anti-inflammatory effects
(155). STAT1 regulates NF-κB
pathway activity. Valproic acid promotes the nuclear translocation
of HDAC3, while inhibiting its activity, which enhances STAT1
expression and increased NF-κB p65 acetylation following spinal
cord injury, thereby mitigating inflammation (156). Simultaneously,
lipopolysaccharide (LPS) stimulation upregulates KAT2B, which
acetylates METTL3 at K14, enhancing METTL3 stability and increasing
Spi2a m6A methylation in macrophages. The methylation of Spi2a
enables its association with IKKβ, which blocks IKK complex
assembly and attenuates NF-κB activation (157).
In diabetic kidney disease, the acetylation
modifications participate in the regulation of inflammatory
responses and renal fibrosis. Clinical data analyses have revealed
that p300 is highly expressed in renal tissues from patients with
diabetic kidney disease and promotes the activation of HIF-related
signaling pathways, thereby exacerbating fibrosis in renal tubular
epithelial cells (158).
p300/CBP-mediated increase in H3K27ac activates
inflammation-related genes, exacerbating the renal inflammatory
microenvironment (159).
Beyond the direct regulation of inflammation-related
gene transcription, cellular metabolic reprogramming has emerged as
another critical mechanism by which acetylation modulates
inflammatory responses. A high-fat diet activates ACLY and promotes
nuclear acetyl-CoA production, thereby activating CBP, which
increases p65 acetylation and heightens inflammation (160). MOF-mediated acetylation of
PRDX1 at K197 maintains redox regulation, while LPS-induced PRDX1
K197ac reduction leads to hydrogen peroxide accumulation, ERK1/2
phosphorylation, glycolysis stimulation, H3S28 phosphorylation and
increased pro-inflammatory cytokine production (161). Collectively, these observations
highlight the significance of lysine acetylation in the chronic
inflammatory diseases through coordinated control of inflammatory
transcription, immune cell function and metabolic
reprogramming.
In AD, reduced global acetylation impairs tau
interaction with chaperones and E3 ligases, hindering
ubiquitin-proteasome system mediated tau clearance and leading to
aggregation. HDAC6 has been also closely associated with amyloid
and tau pathology in AD. Clinical research has revealed that HDAC6
expression is significantly increased in the cerebral cortex of
patients with AD. Mechanistically, HDAC6 may promote Aβ production
by regulating the acetylation status and stability of β-site
amyloid precursor protein cleaving enzyme 1 (BACE1) (168). The HDAC6 inhibitor, CKD-504,
increases protein acetylation, promotes tau-chaperone/E3 binding,
enhances tau degradation and significantly improves cognition in
mouse models of AD (169).
Research indicates that the expression level of HDAC6 is elevated
in patients with AD, which in turn affects the acetylation balance
of α-tubulin and contributes to neuronal dysfunction (170). In another protective mechanism,
deacetylation of NF-κB RelA in response to ischemic stress promotes
pro-apoptotic gene transcription. The HDAC inhibitor, MS-275,
combined with the SIRT1 activator, resveratrol, restores RelA
acetylation in tMCAO and OGD mouse models, providing
neuroprotection (171).
Clinical studies have demonstrated that SIRT1
expression is reduced in adipose tissues from individuals with
obesity and type 2 diabetes mellitus, and decreased SIRT1 levels
are associated with impaired insulin sensitivity. Moreover, adipose
tissue SIRT1 expression exhibits an inverse correlation with the
homeostatic model assessment of insulin resistance index and other
insulin resistance-related parameters, suggesting that
SIRT1-mediated deacetylation regulation may play a critical role in
maintaining glucose homeostasis (172,173). SR18292 selectively inhibits
gluconeogenesis without affecting lipogenesis by increasing PCK1
acetylation and reversing the gluconeogenic pathway, thus showing
anti-diabetic efficacy (174).
Vascular smooth muscle cell (VSMC) dysfunction and hyperacetylation
are exacerbated under type 2 diabetic conditions, thereby promoting
vascular pathology. The inhibition of PCAF reduces the production
of reactive oxygen species in VSMCs under high glucose conditions,
and attenuates vascular injury (175). Clinical research has revealed
that SIRT3 expression is decreased in liver tissues from patients
with metabolic dysfunction-associated steatotic liver disease
(MASLD), accompanied by impaired mitochondrial β-oxidation,
increased reactive oxygen species accumulation and enhanced hepatic
lipid deposition (176).
Further investigations demonstrated that MASLD impairs hepatic
fatty acid metabolism. SIRT3 deacetylates ACSF3, and alleviates
dysregulation of fatty acid metabolism (177).
The US Food and Drug Administration (FDA) has
approved four HDAC inhibitors for clinical use to date. Vorinostat
(SAHA) approved in 2006, is the first HDAC inhibitor introduced
into clinical practice. It is mainly indicated for the treatment of
cutaneous T-cell lymphoma and exerts its pharmacological effects by
inhibiting class I, II and IV histone deacetylases, thereby
enhancing histone acetylation, modulating gene expression, and
ultimately inducing tumor cell differentiation and apoptosis
(178). Romidepsin
(FK228/depsipeptide), which was approved in 2009, is indicated in
patients experiencing recurrence or resistance in cutaneous and
peripheral T-cell lymphomas. Upon entering the cell, romidepsin
enhances acetylation by inhibiting class I HDACs, primarily through
the release of an active moiety (179). Belinostat was approved in 2014
for the treatment of relapsed or refractory peripheral T-cell
lymphoma and functions as a broad HDAC inhibitor (180). Panobinostat (LBH589), a pan
HDAC inhibitor, was approved in 2015 for use in combination
regimens to treat multiple myeloma and mantle cell lymphoma, where
it activates apoptosis-related pathways (181).
Additionally, multiple HDAC inhibitors are under
clinical investigation. Mocetinostat (MGCD0103) is a
benzamide-derived histone deacetylase inhibitor, which specifically
targets HDAC1, HDAC2, HDAC3 and HDAC11; it is currently undergoing
phase I/II clinical evaluation for the treatment of a range of
malignancies, including both Hodgkin's and non-Hodgkin's lymphomas.
Clinical data have demonstrated encouraging efficacy for Hodgkin's
lymphoma (182,183). Pracinostat (SB939) is a
hydroxamate-derived small-molecule inhibitor that acts on class I,
II and IV HDACs. In recognition of its therapeutic potential, FDA
granted it orphan drug designation in 2014 for the treatment of
elderly patients with acute myeloid leukemia and T-cell lymphoma
(184). Resminostat (4SC-201),
an orally available HDAC inhibitor, was evaluated in phase I/II
trials for relapsed or refractory Hodgkin's lymphoma and colorectal
cancer (185). Ricolinostat
(ACY-1215), a selective HDAC6 inhibitor, is currently undergoing
clinical evaluation in combination with bortezomib for myeloma
(186).
Although HDAC inhibitors have demonstrated
therapeutic benefits in the treatment of various types of cancer,
including hematologic malignancies such as T-cell lymphomas and
multiple myeloma, only four have been approved by the FDA, with
indications largely restricted to a limited spectrum of cancers.
Considering the widespread biological functions of acetylation in
diverse pathological contexts, the pace of drug development remains
relatively slow. Notably, the therapeutic exploration of
acetylation-based interventions for non-malignant diseases
continues to represent an unmet need.
The widespread occurrence of lysine acetylation
underscores its critical biological functions. However, current
knowledge of the specific processes and regulatory pathways
associated with lysine acetylation, particularly different cell
types and physiological conditions, remains incomplete. The
detection and quantification methods for lysine acetylation
currently in use are relatively limited, and the specificity and
sensitivity of identifying acetylation sites require further
improvement. Additionally, clinical studies exploring lysine
acetylation as a tool for early disease diagnosis and targeted
therapy are lacking. Future research efforts are warranted to
prioritize investigating the underlying molecular mechanisms that
govern the activity of lysine acetylation enzymes, such as
acetyltransferases and deacetylases, and their regulation in both
normal physiological states and disease-related conditions.
Particular attention needs to be paid to the role and functional
impact of lysine acetylation on specific biological processes,
including development, cellular senescence and tumorigenesis. The
development of more efficient and sensitive analytical techniques
is essential for quantitative and functional studies of lysine
acetylation sites. Additionally, the clinical potential of lysine
acetylation in diagnostics, disease monitoring and therapeutic
applications, particularly in the context of personalized medicine,
warrants further exploration. Investigating the crosstalk of lysine
acetylation with other PTMs can provide valuable information of the
complex regulatory networks controlling cellular signaling.
Strengthening the research in these areas will greatly improve the
understanding of the biological significance of lysine acetylation
and support its application in medical science.
Not applicable.
MZ and YZ conducted the literature review and wrote
the manuscript. HY, JY and YD constructed the figures and were also
involved in the conception of the study. XZ and TC constructed the
tables and were involved in manuscript revision. BL and XG wrote
the manuscript and provided supervision. All authors have read and
approved the final manuscript. Data authentication is not
applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
During the preparation of this manuscript,
AI-assisted tools (ChatGPT) was used to enhance the clarity and
readability of the text. The authors subsequently reviewed,
revised, and edited the AI generated content as necessary and take
full responsibility for the final version of the manuscript.
Not applicable.
The present study was supported by the Noncommunicable Chronic
Diseases-National Science and Technology Major Project (grant no.
2024ZD0530702), the Project supported by the National Natural
Science Foundation of China (grant no. 82404968) and the Natural
Science Foundation of Tianjin Municipality (grant no.
23JCQNJC00750).
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