Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.

List of Abbreviations

Description

5‐fluorouracil

Alanyl‐tRNA synthetase 1

Alanyl‐tRNA synthetase 2

ATP binding cassette subfamily C member 2/3/10

N4‐acetylcytidine

acyl‐CoA oxidase 2

ADP‐ribose

adenylate kinase 2

aldoketoreductase family 1 B10

protein kinase B

aldehyde dehydrogenase 1 family member A1

aquaporin‐1

androgen receptor

androgen receptor splice variant

American Society of Clinical Oncology

autophagy related 14

autotaxin

Bcl‐2 associated X

β‐hydroxybutyrate dehydrogenase 1

beclin 1

polycomb complex protein BMI‐1

bromodomain PHD finger transcription factor

bromodomain‐containing protein 9

brahma‐related gene 1 protein

BUB1 mitotic checkpoint serine/threonine kinase B

cap structure

CREB‐binding protein

cyclin B1

cyclin E2

C‐C motif chemokine receptor 8

cluster of differentiation 39

cluster of differentiation 73

cadherin 1

cyclin‐dependent kinase inhibitor 2B

chromodomain Y‐like 1

chromosome region candidate 2

proto‐oncogene c‐Jun

chaperone‐mediated autophagy

cyclooxygenase 2

carnitine palmitoyltransferase 1A

colorectal cancer

cAMP response element‐binding protein 3

CREB‐binding protein

C‐terminal binding protein 1

connective tissue growth factor

cytochrome P450 61

Discoidin, CUB, and LCCL domain‐containing type I

dimethyl succinate

DNA‐dependent protein kinase catalytic subunit

double PHD zinc finger

double‐strand breaks

end‐binding protein 1

elongation factor 1 alpha2

eleven‐nineteen‐leukemia

alpha‐enolase

esophageal squamous cell carcinoma

E26 transformation specific‐1

coagulation factor X

focal adhesion kinase

fibrillin‐1

ferredoxin 1

fibronectin 1

glucose‐6‐phosphate dehydrogenase

glioma‐amplified sequence 41

general control non‐depressible 5

Gcn5‐related N‐acetyltransferases

GTP binding protein 4

histone acetyltransferase 1

histone acetyltransferases

histone acetyltransferase binding to ORC1

hepatocellular carcinoma

histone deacetylase

hypoxia‐inducible factor 1‐alpha

hypoxia‐inducible factor 2‐alpha

hypoxia‐inducible factor beta

high‐performance liquid chromatography‐tandem mass spectrometry

homologous recombination

hypoxia response elements

heat shock protein 90

interleukin 10

interleukin 6

induced pluripotent stem cell

interferon regulatory factor 1

integrin subunit beta 3

Jumonji Domain Containing 6

lysine acetyltransferase

lysine acetyltransferase 2A

lysine β‐hydroxybutyrylation

lysine butyrylation

lysine crotonylation

lysine‐specific histone demethylase 1A

lysine glutarylation

lysine 2‐hydroxyisobutyrylation

lysine lactylation

lysine malonylation

lysine propionylation

lysine succinylation

beta‐lactamase‐like protein

laminin subunit gamma 2

lipocalin 2

lactate dehydrogenase A

5‐methylcytosine

N6‐methyladenosine

MDM2 proto‐oncogene

monocyte‐derived macrophages

malic enzyme 2

methyltransferase‐like protein 16

methyltransferase‐like protein 3

mitochondrial fission factor

matrix metallopeptidase 2

males absent on the first

MOZ related factor

monocytic leukemia zinc finger protein

meiotic recombination 11

MRE11‐RAD50‐NBS1

metastasis‐associated protein 2

methylation transfer domain

methylenetetrahydrofolate dehydrogenase 1

MYC proto‐oncogene

Moz, Ybf2/Sas3, Sas2, Tip60

N‐acetyltransferase 10

Nijmegen breakage syndrome protein 1

non‐homologous end‐joining

nicotinamide mononucleotide adenylyltransferase 1

Notch receptor 3

nucleophosmin 1

non‐synonymous single nucleotide polymorphisms

NOP2/Sun RNA methyltransferase family member 2

nuclear and spindle‐associated protein 1

3‐oxoacid Co A‐transferase

cyclin‐dependent kinase inhibitor 1A

E1A binding protein P300

tumor protein 53

phosphatidylinositol 3‐kinase regulatory subunit 1

pancreatic adenocarcinoma

p300/CBP‐associated factor

programmed cell death 1 ligand 1

pancreatic ductal adenocarcinoma

period circadian regulator 1

protein kinase R‐like ER kinase

phosphoglycerate kinase 1

phosphatidylinositol 3‐kinase

phosphatidylserine decarboxylase

protein kinase A

protein‐protein interactions

pentose phosphate pathway

protein kinase cAMP‐dependent catalytic‐alpha

protein arginine methyltransferase 5

post‐translational modifications

p53 up‐regulated modulator of apoptosis

retinoic acid

RNA interference/clustered regularly interspaced short palindromic repeats

RNA polymerase subunit α

regulatory associated protein of mTOR complex 1

rubicon‐like autophagy enhancer

Septin2

serine hydroxymethyltransferase‐2

SIN3 transcription regulator family member A

sirtuin

sterol regulatory‐element binding protein 1a

STIP1 homology and U‐box containing protein 1

TATA‐box binding protein associated factor 1

tricarboxylic acid

TEA domain transcription factor 1

mitochondrial transcription factor A

transforming growth factor‐β

transforming growth factor‐β1

translocase of the inner mitochondrial membrane 23

tumor‐infiltrating myeloid cells

Tat‐interacting protein of 60 kDa

transketolase

tumor protein p53

transcriptional replication conflicts

dual specificity protein kinase TTK

UV radiation resistance‐associated gene protein

vacuolar protein sorting 34

Yes‐associated protein

Y‐box binding protein 1

Yaf9, ENL, AF9, Taf14, Sas5

YTH domain‐containing family protein 1

YTH domain‐containing family protein 2

tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein zeta

Yin Yang 1

Zn 2+ binding group

alpha‐ketoglutarate dehydrogenase

β‐hydroxybutyrate

INTRODUCTION

Emerging research increasingly reveals that essential cellular processes, including intracellular signal transduction, metabolic regulation, oxidative stress response, and DNA damage repair, are not exclusively reliant on protein abundance. Rather, these processes are profoundly influenced by post‐translational modifications (PTMs) of proteins, which alter their structure and function. These modifications play a pivotal role in the pathogenesis of diseases such as inflammation [ 1 ], metabolic disorders [ 2 ], and are particularly critical in the initiation and progression of tumors [ 3 ].

PTMs are essential for regulating protein functions by adding or removing chemical groups such as acetyl, succinyl, crotonyl, and lactyl to protein amino acid residues. These modifications induce structural and property changes, impacting spatial conformation, stability, activity state, subcellular localization, and interactions with other cellular molecules. PTMs play a significant role in various diseases, particularly cancer [ 1 , 4 ]. To date, over 600 PTMs have been identified [ 5 ]. Advancements in proteomics and biochemical technologies have facilitated the discovery and characterization of novel PTMs, among which a significant proportion are metabolically derived short‐chain acylation modifications (with acyl groups containing fewer than six carbon atoms) [ 6 ], including butyrylation [ 7 ], succinylation [ 8 ], crotonylation [ 9 ], malonylation [ 10 ], glutarylation [ 11 ], 2‐hydroxyisobutyrylation [ 12 ], β‐hydroxybutyrylation [ 13 ], and lactylation [ 14 ]. These findings have profoundly expanded the potential complexity of the histone code. These emerging PTMs differ from traditional acylation modifications in structure, physicochemical properties, function, and regulatory mechanisms.

Recent research indicates that abnormalities in these short‐chain acyl‐PTMs are often associated with tumor progression, leading to changes in protein characteristics and the impairment of biological functions, thereby contributing to tumor pathogenesis [ 15 , 16 , 17 ]. For example, under hypoxic conditions, elevated levels of crotonylation in hepatic cancer regulate the nuclear localization of nuclear lamin A by modifying lysine residues at positions 265 and 270, thereby promoting hepatocellular carcinoma (HCC) cell proliferation [ 15 ]. Similarly, 2‐hydroxyisobutyrylation is significantly increased in esophageal cancer, enhancing the stability of N‐acetyltransferase 10 (NAT10) at lysine 823, thus facilitating esophageal cancer invasion and metastasis [ 16 ]. Elevated lactylation levels are detected in pancreatic adenocarcinoma (PAAD) patients, correlating with poor prognosis; specifically, lactylation at lysine 128 of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) enhances its nuclear localization and enzymatic activity, supporting pancreatic cancer cell survival under glucose deprivation [ 17 ]. Hence, short‐chain acyl‐PTMs play a pivotal role in tumor initiation and progression. Understanding the mechanisms underlying these short‐chain acylation modifications may unveil new therapeutic targets, leading to the development of more precise personalized treatment strategies. The knowledge lays a critical scientific groundwork for innovative treatment modalities and the establishment of diagnostic and therapeutic protocols, potentially driving progress in cancer therapy and ultimately improving patient survival rates and quality of life.

We analyzed the research from the perspective of epigenetic modifications, summarizing the mechanisms of action of eight short‐chain acyl‐PTMs: butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2‐hydroxyisobutyrylation, β‐hydroxybutyrylation, and lactylation in the context of tumors. We explored their roles in tumor genomic stability, gene transcription, protein stability, enzyme activity, and protein nuclear localization. Additionally, we provide a comprehensive overview of their biological functions in tumors and the current status of preclinical and clinical research on inhibitors targeting these PTM‐related regulatory enzymes. We aim to offer fresh insights and references for the diagnosis, treatment, and development of anti‐tumor drugs.

OVERVIEW OF SHORT‐CHAIN ACYL‐PTMs

Recent advancements have substantially enhanced our understanding of traditional PTMs such as methylation, phosphorylation, glycosylation, acetylation, and ubiquitination. The progress in high‐resolution chromatography‐mass spectrometry techniques has facilitated the ongoing discovery of short‐chain acyl‐PTMs, including butyrylation [ 7 ], succinylation [ 8 ], crotonylation [ 9 ], and lactylation [ 14 ]. These modifications are formed by the attachment of short‐chain acyl groups (fewer than six carbon atoms, excluding formyl or acetyl groups) to the ε‐N of lysine residues in proteins, and are classified as short‐chain acyl‐PTMs [ 18 ]. These emerging short‐chain acyl‐PTMs extend their influence beyond histones to non‐histone proteins, significantly impacting various biological processes such as tumor cell metabolism [ 3 ], tumor immunity [ 19 ], and signal transduction [ 20 ]. Consequently, these short‐chain acyl‐PTMs have garnered considerable attention in recent years within the field of PTMs (Figure 1A ).

The short‐chain acyl modifications have primarily been identified through high‐performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS). Based on the detected mass shifts and subsequent experimental validation, this approach allows researchers to determine the specific modification types responsible for these mass shifts. For example, in 2007, Chen et al. simultaneously identified lysine propionylation (Kpr) and butyrylation (Kbu) through HPLC‐MS/MS analysis in a proteomic study, which feature extended hydrocarbon chains that confer greater hydrophobicity and steric bulk to lysine residues compared to acetylation [ 7 ]. Subsequent studies have revealed their critical roles in gene expression and chromatin remodeling [ 21 , 22 ]. However, the functional role of propionylation in tumor progression remains unexplored, with no studies to date specifically addressing its mechanistic contributions to oncogenesis. In 2011, Zhang et al. identified the presence of lysine succinylation (Ksuc) modification in Escherichia coli isocitrate dehydrogenase on the basis of a mass shift of +100.0186 Da at the lysine residue through integrated approaches including HPLC‐MS/MS analysis, PTMap‐based sequence alignment, and manual validation, thereby defining it as a novel PTM [ 8 ]. Recent studies suggest that Ksuc plays a critical role in regulating tumor cell metabolism [ 23 ], managing oxidative stress [ 24 ], and modulating the tumor immune microenvironment [ 25 ]. The succinyl group alters the charge of lysine residues from positive to negative and introduces substantial steric hindrance due to its bulky structure, which can significantly perturb protein conformation and thereby modulate protein function [ 26 ]. Then, Tan et al. described lysine crotonylation (Kcr) in human histones, characterized by a mass shift of +68.0230 Da, as a novel histone PTM through a systematic proteomic approach integrating multidimensional PTM profiling [ 9 ]. Furthermore, Kcr has a rigid planar structure different from other acyl groups, is primarily located in active gene promoters and potential enhancer regions, and participates in tumor metabolism and immune processes [ 9 , 27 ]. Subsequently, Peng et al. employed high‐throughput proteomic analysis in mammals and Escherichia coli to reveal lysine malonylation (Kma), which induces a +86.00 Da mass shift of the modified peptide [ 10 ]. Studies have demonstrated that Kma is an evolutionarily conserved acyl modification essential for energy metabolism, inflammation signaling in macrophages, and immune regulation, closely associated with tumor metabolism regulation and metastasis [ 10 , 28 , 29 ]. In 2014, Tan et al. systematically identified lysine glutarylation (Kglu) through integrated immunoblotting and mass spectrometry analyses, characterized by a mass shift of approximately +114 Da of the modified peptide [ 11 ]. More importantly, Kglu plays a key role in nucleosome assembly, chromatin architecture remodeling, and transcriptional reprogramming [ 30 ]. Mechanistically analogous to succinylation, both malonylation and glutarylation, characterized by their acidic acyl groups, induce charge inversion at lysine residues (from positive to negative). Such electrostatic perturbations fundamentally alter protein conformational dynamics and intermolecular interaction networks, thereby modulating biological activity [ 18 ]. As PTM research progresses, two novel hydroxyl‐containing types have emerged: lysine 2‐hydroxyisobutyrylation (Khib) and lysine β‐hydroxybutyrylation (Kbhb), both of which contain hydroxyl groups, enabling the modified lysine residues to form hydrogen bonds with other molecules [ 12 , 13 ]. In 2014, Dai et al. identified a +86.0354 Da mass shift on lysine residue of histone H4 through proteomic analysis of mouse testis cells, leading to the discovery of 2‐hydroxyisobutyrylation (Khib) [ 12 ]. This modification is prevalent on histones and is associated with glucose metabolism, amino acid synthesis, and glycolysis, showing significance in regulating tumor metabolism and metastasis [ 31 , 32 ]. β‐Hydroxybutyrylation, also known as 3‐hydroxybutyrylation, was initially described in 2016 [ 13 ]. Specifically, Xie et al. analyzed tryptic digests of core histones isolated from HEK293 cells, identifying a +86.0368 Da mass shift on lysine residue of histone H3, and they demonstrated that the shift derives from β‐hydroxybutyrylation [ 13 ]. Further analysis of Kbhb modification substrates suggests its involvement in chromatin remodeling, transcription regulation, DNA damage repair, and diverse cellular functions, closely linked to tumor cell proliferation and core metabolic regulation [ 33 , 34 ]. A groundbreaking discovery in 2019 introduced lysine lactylation (Kla), significantly advancing the field [ 14 ]. The initial evidence for histone Kla originated from a +72.021 Da mass shift observed on lysine residues of hydrolyzed peptides from core histones in human MCF‐7 cells, and subsequent experiments confirmed that this shift results from the addition of a lactyl group to lysine [ 14 ]. The finding not only enhances understanding of lactate's function but also urges a reevaluation of the classic Warburg effect in tumor research. Lactylation could create steric hindrance, impacting amino acid interactions or protein folding, and consequently, protein function [ 35 ]. Given the prevalent metabolic irregularities in the tumor microenvironment and elevated lactate levels due to the Warburg effect, it is plausible that Kla serves as a critical link between lactate, tumor metabolism, and patient prognosis. Lactylation modification represents the forefront of PTM research, with growing evidence of its involvement in regulating tumor metabolism, tumor cell proliferation, and metastasis, particularly in influencing key aspects such as tumor cell drug resistance and immune evasion [ 36 , 37 ].

Overall, emerging short‐chain acyl‐PTM mechanisms have garnered increasing interest among researchers and have become a focal point in contemporary studies of protein PTMs. Recent research indicates a strong correlation between abnormal levels of short‐chain acyl‐PTMs and the onset and progression of tumors (Figure 1B ). Investigating these innovative PTM pathways is essential for uncovering the fundamental mechanisms driving cancer development, identifying novel therapeutic targets, and enhancing individualized treatment for cancer patients.

REGULATORY ENZYMES OF SHORT‐CHAIN ACYL‐PTMs

In protein biology, a novel class of enzymes associated with PTMs has emerged. These PTMs, present in newly synthesized proteins, are characterized by their reversible and dynamic nature, primarily regulated through enzymatic processes, though non‐enzymatic mechanisms also contribute. Enzymes involved in these reactions can be categorized into three main groups: acetyltransferases, known as “Writers”; deacetylases, referred to as “Erasers”; and proteins that recognize PTMs, labeled as “Readers”. This review provides a concise overview of eight emerging PTM regulatory enzymes, including those for butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2‐hydroxyisobutyrylation, β‐hydroxybutyrylation, and lactylation (Figure 2 ). Despite structural differences among these modifications, common regulatory enzymes, such as E1A‐binding protein of 300 kDa (p300)/CREB‐binding protein (CBP), Tat‐interacting protein of 60 kDa (TIP60), members of the histone deacetylase (HDAC) family, and the sirtuin (SIRT) family, are often utilized. Further investigation into these regulatory enzymes promises to enhance our understanding of the roles and mechanisms governing these innovative PTMs, potentially identifying new targets for cancer therapeutics.

Epigenetic writers

Acyltransferase “writers” are responsible for transferring acyl groups from acyl‐CoA donors, such as butyryl‐, succinyl‐, malonyl‐, crotonyl‐, glutaryl‐, hydroxyisobutyryl‐, β‐hydroxybutyryl‐, and lactyl‐CoA, to amino acid side chains like lysine or serine. Histone acetyltransferases (HATs) not only facilitate acetylation but also catalyze various acylation modifications. HATs are classified into three primary families based on their sequence and structural characteristics: (1) the p300/CBP family; (2) the Moz, Ybf2/Sas3, Sas2, Tip60 (MYST) family, including TIP60, monocytic leukemia zinc finger protein (MOZ), MOZ related factor (MORF), histone acetyltransferase binding to ORC1 (HBO1) and males absent on the first (MOF), which are known as lysine acetyltransferase (KAT) 5, KAT6A, KAT6B, KAT7 and KAT8, respectively; (3) the Gcn5‐related N‐acetyltransferases (GNAT) family, comprising histone acetyltransferase 1 (HAT1), general control non‐depressible 5 (GCN5), p300/CBP‐associated factor (PCAF), and others [ 19 ]. These families' members are predominantly localized within the cell nucleus [ 39 ]. Notably, p300 and CBP, collectively known as p300/CBP, exhibit high homology in amino acid sequences and functions, enabling them to catalyze a wide array of acylation modifications [ 40 ]. The catalytic core of the p300/CBP complex includes the bromodomain, HAT domain, cysteine‐ and histidine‐rich regions (involving PHD and RING domains), and the ZZ‐type zinc finger domain [ 41 ]. The MYST family includes a MYST domain, typically characterized by an HAT functional domain, a C2HC zinc finger, and an acetyl‐CoA binding site. The conserved HAT domain acts as the enzymatic catalytic region, interacting with acetyl‐CoA and substrates [ 42 ]. TIP60, also known as KAT5, is extensively studied for its pivotal roles in DNA damage repair, transcription regulation, and cell cycle control. The GNAT family features a conserved N‐terminal GNAT domain of approximately 140 amino acids, composed of five helices and four β sheets interconnected by linkers [ 43 ]. GCN5 protein comprises three distinct domains: the C‐terminal Bromodomain, the N‐terminal PCAF domain, and the catalytically active HAT domain, which is conserved and responsible for acetyl‐CoA recognition [ 44 ].

“Writers” have demonstrated the capacity to attach various acyl groups to specific amino acid residues such as lysine (K) and serine (S), thereby impacting protein structure and functionality [ 3 , 38 , 45 ]. For example, p300 facilitates the lactylation of histone H3K18, enhancing the expression of cell cycle‐related genes dual specificity protein kinase TTK ( TTK ) and BUB1 mitotic checkpoint serine/threonine kinase B ( BUB1B ), and promoting tumor growth in pancreatic ductal adenocarcinoma [ 46 ]. Additionally, p300 acetylates serine 46 of tumor protein 53 (p53) in colorectal cancer (CRC) cells, leading to decreased p53 levels, increased p53‐dependent glycolytic activity, and heightened CRC cell proliferation under metabolic or DNA damage‐induced stress [ 47 ]. However, the specific acyltransferases responsible for these translational modifications require further exploration. Notably, research has identified 3‐oxoacid CoA‐transferase 1 (OXCT1), a novel succinyltransferase that targets the crucial amino acid site G424 and is associated with the ketone body metabolism enzyme [ 48 ]. OXCT1 mediates the succinylation modification of the K284 site of the serine beta‐lactamase‐like protein (LACTB), inhibiting its protease activity and thereby promoting hepatic cancer progression [ 48 ]. Similarly, recent studies have discovered four novel lactyltransferases: alanyl‐tRNA synthetase 1 (AARS1), alanyl‐tRNA synthetase 2 (AARS2), and acetyltransferases KAT8 and HBO1, each with lactyltransferase activity distinct from their conventional roles in cancer progression [ 49 , 50 , 51 , 52 , 53 ]. Ju et al. reported that AARS1 functions as a lactyltransferase, directly utilizing lactate to catalyze lactylation of key components of the Hippo signaling pathway, thereby activating downstream gene transcription and promoting gastric cancer cell proliferation [ 50 ]. In addition, Xie et al. characterized KAT8 as a pan‐lactyltransferase that enhances protein translation efficiency by lactylating lysine 408 of the eukaryotic translation elongation factor 1alpha2 (eEF1A2), thus fostering CRC progression [ 52 ]. Moreover, Niu et al. discovered that HBO1 acts as a “Writer” of histone lactylation, with E508 as a critical enzymatic site, mediating histone H3K9la to regulate the transcription of genes like aquaporin‐1 ( AQP1 ), laminin subunit gamma 2 ( LAMC2 ), and coagulation factor X ( F10 ), ultimately promoting cervical cancer progression [ 53 ]. Furthermore, GNAT13, a new acetyltransferase in the GNAT family found in prokaryotes, lactylates Lys173 of the RNA polymerase subunit α (RpoA), inhibiting Streptococcus mutans biofilm biosynthesis [ 54 ]. As research into translational modifications advances, more specific acyltransferases are expected to be identified, laying the groundwork for elucidating the biological functions of these modification codes.

Epigenetic erasers

The term “Erasers” primarily refers to the HDAC family, which catalyzes the removal of acetyl modifications on lysine residues, thereby influencing protein stability and enzymatic activity. Notable examples include SIRT5, which desuccinylates p53 at K120, inhibiting its transcriptional activity [ 55 ], and transketolase (TKT), activating it post‐demalonylation [ 56 ]. Additionally, SIRT7 desuccinylates protein arginine methyltransferase 5 (PRMT5) at K387, reducing its ubiquitination and degradation [ 57 ], while HDAC3 decrotonylates the end‐binding protein 1 (EB1), enhancing its microtubule‐binding capability [ 58 ]. Currently, 18 HDAC isozymes have been identified in humans, classified into four classes based on amino acid sequences, homology, molecular weight, and cellular localization: Class I (HDAC1‐3, HDAC8, primarily nucleus‐localized); Class IIa (HDAC4, 5, 7, 9, found in nucleus and cytoplasm) and Class IIb (HDAC6, 10, mainly cytoplasmic); Class III (SIRT1‐7, present in cytoplasm, nucleus, and mitochondria, with NAD + as the catalytic site); Class IV (HDAC11, existing in nucleus and cytoplasm) [ 59 , 60 ]. The 11 subtypes within Classes I, IIa, IIb, and IV are Zn 2+ ‐dependent enzymes, featuring a conserved active site structured as a tunnel‐shaped pocket housing the Zn 2+ ion [ 61 ]. The Zn 2+ ‐dependent deacetylation mechanism in HDACs parallels that of metalloproteases and serine proteases [ 62 ]. Initially, Zn 2+ interacts with the carbonyl oxygen of acetylated lysine residues, inducing polarization and activating the electrophilic carbon. A catalytic water molecule binds to Zn 2+ , and histidine residue side chains form hydrogen bonds, rendering the water molecule highly nucleophilic. The nucleophilic water attacks the carbonyl carbon of acetylated lysine, forming a tetrahedral oxyanion intermediate. Deacetylation completes with proton transfer from the histidine side chain to the lysine's amino nitrogen, producing acetic acid salt and lysine as byproducts [ 63 ]. Class III SIRTs are NAD + ‐dependent protein deacetylases, essential for reversing acetyl‐lysine modifications. The NAD⁺‐dependent deacetylation mechanism involves NAD + and acetylated lysine residues reacting to form an ADP‐ribose (ADPR)‐peptide‐imine intermediate. NAD + consumption, combined with the acetylated protein substrate and water, results in acetyl group removal at the N(ε) position, yielding nicotinamide and 2'‐AADPR as byproducts. The process described above allows SIRTs to respond dynamically to fluctuations in cellular NAD + and nicotinamide levels [ 64 ]. HDACs involved in newly identified PTMs include HDAC1‐4, 6, SIRT1‐7. Deacetylases associated with 2‐hydroxyisobutyrylation include not only HDAC1‐3 and SIRT7 but also Rpd3p and Hos3p in yeast, as well as CobB in prokaryotes [ 65 , 66 ].

Epigenetic readers

PTMs on proteins are identified and interpreted by specialized proteins known as “Readers”, which contain specific functional domains [ 67 ]. These “Readers” play a pivotal role in recognizing histone covalent modifications, central to the mechanism of epigenetic regulation. To date, among short‐chain acylation modifications in our review, specific “Readers” have been identified for all modifications except malonylation and 2‐hydroxyisobutyrylation, whose recognition mechanisms remain to be elucidated [ 68 , 69 , 70 , 71 ]. Previous studies have demonstrated that bromodomain‐containing proteins bromodomain‐containing protein 9 (BRD9), chromosome region candidate 2 (CECR2), TATA‐box binding protein associated factor 1 (TAF1), as well as the YEATS (Yaf9, ENL, AF9, Taf14, Sas5) domain‐containing protein AF9, can function as “Readers” for histone butyrylation modifications [ 72 , 73 ]. To date, only one protein acting as a succinylation “Reader” has been identified: glioma‐amplified sequence 41 (GAS41). GAS41 features a YEATS domain that detects Ksuc through the formation of specific salt bridges with protonated histidine residues, a mechanism similar to that of Yaf9 [ 74 ]. The group of proteins serving as crotonylation “Readers” includes members of the YEATS domain family (such as human AF9, YEATS2, ENL, and yeast Taf14 and Sas5) and the double PHD zinc finger (DPF) domain family (DPF2, MOZ) [ 75 , 76 , 77 , 78 , 79 ]. The evolutionarily conserved YEATS domain is present in four human proteins (ENL, AF9, GAS41, and YEATS2) and three yeast proteins (Sas5, Taf14, and Yaf9), contributing to processes such as chromatin remodeling, histone modification, histone variant deposition, and transcriptional regulation [ 77 , 80 ]. Additionally, structural studies of the DPF domains in MOZ and DPF2 have revealed their ability to specifically recognize histone crotonylation modifications [ 79 ]. Notably, recent breakthroughs in epigenetic recognition mechanisms have led to the identification of specific “Readers” for β‐hydroxybutyrylation and lactylation modifications [ 69 , 70 , 71 ]. Among these, eleven‐nineteen‐leukemia (ENL) was identified as the first‐reported β‐hydroxybutyrylation “Reader”, which recognizes H3K9bhb at gene promoters through its YEATS domain, thereby promoting the transcription of oncogenes such as MYC proto‐oncogene ( MYC ) and driving hepatocellular carcinoma progression [ 69 ]. In the field of lactylation, brahma‐related gene 1 protein (Brg1) was revealed as the first‐reported histone lactylation “Reader”, which can regulate induced pluripotent stem cell (iPSC) reprogramming [ 70 ]. A subsequent study identified DPF2 as a novel lactylation “Reader” that specifically binds H3K14la to activate tumorigenesis‐associated gene expression programs, ultimately accelerating cervical cancer cell proliferation [ 71 ]. These discoveries not only expand the theoretical framework of short‐chain acyl‐PTMs recognition but also provide novel therapeutic targets for cancer treatment strategies focusing on the “PTM‐Reader” axis.

MECHANISM OF SHORT‐CHAIN ACYL‐PTMs MEDIATING TUMORIGENESIS AND DEVELOPMENT

Short‐chain acyl‐PTMs impact genomic stability in cancer cells

Genomic instability is a hallmark of cancer cells, making the prompt repair of damaged DNA essential for their survival [ 81 , 82 ]. Advances in PTM research have revealed that short‐chain acyl‐PTMs play a vital role in the DNA damage response of cancer cells, significantly influencing their ability to withstand radiotherapy and chemotherapy [ 56 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. Various short‐chain acyl‐PTMs, such as succinylation, crotonylation, malonylation, and lactylation, exhibit distinct regulatory mechanisms in DNA damage repair. These modifications can target both histones and non‐histones, affecting processes like DNA homologous recombination (HR) repair and non‐homologous end‐joining (NHEJ) repair, modulating genome stability, thereby regulating tumor malignant phenotypes and chemo/radiotherapy sensitivity (Figure 3 and Table 1 ). Understanding the regulatory mechanisms of these short‐chain acyl‐PTMs in the DNA damage repair of cancer cells is essential. Such knowledge could reveal vulnerabilities in cancer, offering new avenues for treatment, especially for drug‐resistant tumors.

Histone lysine desuccinylation plays a significant role in DNA damage repair and maintaining genomic stability in tumor cells. For example, Li et al. discovered that SIRT7, an NAD + ‐dependent histone desuccinylase, is recruited to double‐strand breaks (DSBs) to catalyze H3K122 desuccinylation. This process facilitates chromatin condensation and DSB repair, enhancing the survival of tumor cells such as breast cancer, osteosarcoma, CRC, and hepatic cancer [ 84 ]. Conversely, crotonylation impacts DSB‐induced transcriptional inhibition, DSB repair, and DNA replication stress responses [ 83 ]. Hao et al. demonstrated that crotonylation participates in replication stress responses in osteosarcoma and CRC cells. SIRT1‐mediated removal of histone H2AK119 crotonylation resolves replication stress‐induced transcriptional replication conflicts (TRCs), safeguarding genomic stability [ 85 ]. In osteosarcoma, the crotonyl‐CoA hydratase chromodomain Y‐like 1 (CDYL1) is recruited to DSBs, downregulating H3K9 crotonylation around DSBs and promoting DNA HR repair [ 86 , 87 ]. Moreover, DNA damage also affects the level of crotonylation modification. Liao et al. reported that SIRT6 mediates the reduction of H3K27 crotonylation during DNA damage in CRC cells, in preparation for DNA damage repair [ 88 ]. The intricate regulatory role of crotonylation in cancer DNA damage processes underscores the necessity for further in‐depth research.

Alongside histone modifications, crotonylation, malonylation, and lactylation contribute to the regulation of DNA damage processes by targeting non‐histone proteins like DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs), TKT, and meiotic recombination 11 (MRE11). For instance, Han et al. demonstrated that crotonylation of DNA‐PKcs at K525 by histone acetyltransferase GCN5 in cervical cancer cells amplified DNA‐PKcs DNA binding activity. This enhancement facilitated NHEJ repair and reduced cancer radiosensitivity [ 89 ]. In CRC, decreased malonylation prevented DNA damage through SIRT5‐mediated demalonylation of TKT at K281, supporting nucleotide synthesis and safeguarding against DNA damage, ultimately conferring resistance to 5‐fluorouracil (5‐FU) [ 56 ]. Recent findings have linked lactylation of proteins to DNA damage repair and chemotherapy resistance in tumor cells. For example, Chen et al. discovered that lactylation of HR protein MRE11 at K673 by CBP boosted DNA binding capacity, facilitating DNA repair and contributing to chemotherapy resistance in breast cancer, CRC, and osteosarcoma. Conversely, inhibiting MRE11 lactylation hindered the hyperactivation of HR repair, enhancing chemotherapy sensitivity in cancer cells [ 90 ]. Additionally, in gastric cancer, TIP60‐mediated lactylation of Nijmegen breakage syndrome protein 1 (NBS1) at K388 facilitated the assembly of the DNA damage repair complex MRE11‐RAD50‐NBS1 (MRN) and various HR repair proteins at DNA double‐strand break sites, promoting DNA repair and tolerance to chemotherapy agents like cisplatin and etoposide [ 91 ]. Given the prevalence of the Warburg effect in most tumors, the revelation that lactylation regulates HR repair sheds new light on the interplay between cell metabolism and DNA repair pathways, offering a potential therapeutic avenue for lactate‐enriched cancers.

These findings underscore the critical role of short‐chain acyl‐PTMs in modulating DNA damage repair pathways, impacting genomic stability, and influencing cancer progression. PTMs extend beyond histone modifications to include non‐histone proteins in DNA damage regulation. However, further research is essential to elucidate and substantiate these regulatory mechanisms. A comprehensive understanding of the functional significance of short‐chain acyl‐PTMs in DNA damage repair holds significant implications for developing innovative cancer treatment strategies, particularly in combating anti‐tumor drug resistance.

Short‐chain acyl‐PTMs affect gene transcription in cancer cells

Precise regulation of gene transcription is a central driver of tumorigenesis and progression [ 92 ]. Recent discoveries of short‐chain acyl‐PTMs, such as succinylation, crotonylation, β‐hydroxybutyrylation, and lactylation, have revealed their critical role in constructing complex transcriptional regulatory networks at the epigenetic level, including dynamically remodeling chromatin architecture and modulating transcription factor activity, thereby rewiring oncogenic transcriptional programs (Figure 4 and Table 2 ). Specifically, PTMs can enhance DNA accessibility by altering histones, which favors gene transcription [ 19 ]. For instance, modifications such as Kla, Kbhb, and Khib introduce hydroxyl groups on lysine residues, increasing their hydrogen bonding capacity and facilitating the recruitment of chromatin remodeling factors, transcription factors, and histone modification factors [ 18 , 19 ]. This ultimately promotes chromatin recombination and gene regulation. Moreover, Ksuc modification alters the charge of lysine residues from positive to negative at physiological pH, reducing DNA‐histone affinity and affecting nucleosome stability and the dissociation of DNA and proteins [ 18 , 19 ]. Another modification, introducing negatively charged crotonyl groups, decreases the positive charge, enhancing their binding with DNA and interactions with transcription factors [ 19 , 93 ]. Additionally, short‐chain acyl‐PTMs extend to non‐histone proteins, including p53, C‐terminal binding protein 1 (CTBP1), and other transcription factors, modulating their transcriptional activity and regulating the expression of downstream target genes [ 55 , 94 ]. These insights underscore the critical role of short‐chain acyl‐PTMs in gene transcription, which are pivotal in shaping cancer progression. Further research is essential to elucidate these regulatory mechanisms, providing a comprehensive understanding of the functional significance of PTMs. This knowledge holds significant implications for developing innovative cancer treatment strategies, particularly in overcoming anti‐tumor drug resistance.

Succinylation can significantly impact gene transcription by modifying lysine residues on histones and non‐histone proteins, such as transcription factors, thereby influencing their transcriptional activity (Figure 4A ). Research by Zorro Shahidia and colleagues revealed that succinylation of H3K122, mediated by p300/CBP, can destabilize nucleosomes, potentially displace histone octamers from DNA, and enhance DNA accessibility. This mechanism is particularly crucial in regulatory regions like the transcription start site, where H3K122suc can enhance the binding of transcription factors, thus activating and sustaining transcription [ 118 ]. Conversely, SIRT5 (or SIRT7)‐mediated desuccinylation of H3K122suc can lead to chromatin stabilization and compaction, ultimately reducing DNA accessibility [ 84 , 118 ]. In hepatic cancer, HAT1 plays a significant role in succinylation of histone H3 at K122, facilitating epigenetic regulation and the expression of genes such as CREB‐binding protein ( CREBBP ), bromodomain PHD finger transcription factor ( BPTF ), and regulatory associated protein of mTOR complex 1 ( RPTOR ) in tumor cells, thereby promoting tumorigenesis [ 117 ]. In gliomas, the interaction between the alpha‐ketoglutarate dehydrogenase (α‐KGDH) complex and lysine acetyltransferase 2A (KAT2A, also known as GCN5) in tumor cell nuclei induces succinylation of histone H3K79 through succinyl‐CoA, leading to the transcription of oncogenes like phosphatidylinositol 3‐kinase reregulatory subunit 1 ( p85α ), DNA‐PKcs , and proto‐oncogene c‐Jun ( c‐Jun ), fostering glioma cell proliferation [ 114 , 115 ]. Similarly, in pancreatic ductal adenocarcinoma (PDAC), KAT2A regulates H3K79 succinylation in the promoter region of tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein zeta ( YWHAZ , encoding 14‐3‐3ζ protein), enhancing 14‐3‐3ζ expression, inhibiting β‐catenin degradation, and promoting β‐catenin‐dependent gene expression, consequently boosting tumor cell glycolysis, proliferation, and invasion [ 116 ]. Succinylation can also modify transcription factors and participate in gene transcription regulation. For example, in prostate cancer, KAT2A mediates succinylation at K46 and K280 sites of the transcriptional repressor CTBP1, resulting in the inhibition of its suppressive activity on cadherin 1 (CDH1) transcription and the upregulation of CDH1 expression, facilitating CDH1‐mediated prostate cancer metastasis [ 94 ]. Furthermore, desuccinylation of the p53 protein at K120 in CRC weakens its enrichment in the promoters of target genes, such as cyclin‐dependent kinase inhibitor 1A ( p21 ), p53 up‐regulated modulator of apoptosis ( PUMA ), Bcl‐2 associated X ( BAX ), and MDM2 proto‐oncogene ( MDM2 ), thereby inhibiting the transcription of these target genes and p53‐induced cell apoptosis [ 55 ]. These results suggest that, beyond intervening in histone succinylation modifications, disrupting succinylation modifications on non‐histone proteins like transcription factors could impede the transcription of oncogenes, potentially impeding tumor progression. This highlights the importance of understanding and targeting PTMs for developing innovative cancer treatment strategies.

Histone crotonylation is recognized for enhancing gene expression (Figure 4B ). For instance, in metastatic CRC tissues, H3K27 crotonylation on the E26 transformation‐specific‐1 ( ETS1 ) promoter region elevates its expression. The interaction between LINC00922 and SIRT3 hinders SIRT3's translocation to the ETS1 promoter, increasing H3K27 crotonylation and thus ETS1 expression, which promotes CRC cell invasion and migration both in vitro and in vivo [ 96 ]. Another study on CRC revealed that H3K18 crotonylation can prompt autotaxin ( ATX ) transcription. Mechanistically, the heterodimer formed by hypoxia‐inducible factor 2‐alpha (HIF‐2α) and hypoxia‐inducible factor beta (HIF‐β) binds directly to hypoxia response elements (HRE) on the ATX promoter, recruiting p300/CBP to perform acetyltransferase activity, resulting in heightened H3K18 crotonylation and inducing ATX expression, thereby promoting CRC cell migration [ 95 ]. However, Liu et al. found that depleting H3K27cr on chromatin can mediate the repression of gene transcription in CRC cells. Concretely, H3K27cr in chromatin is preferentially recognized by the YEATS domain of GAS41, which forms a complex with SIN3 transcription regulator family member A (SIN3A) and HDAC1, recruited by the oncogenic transcription factor MYC to repress genes like p21 and cyclin‐dependent kinase inhibitor 2B ( CDKN2B ), thereby fostering tumor proliferation [ 97 ]. In summary, the effects of histone crotonylation on gene transcription are complex, including promoting the transcription of some genes or causing repression of gene transcription, to participate in the regulation of cancer progression.

Beta‐hydroxybutyrylation also facilitates gene transcription by modifying histones and plays a pivotal role in tumorigenesis (Figure 4C ). Huang and colleagues demonstrated in vitro that acetyltransferase p300 catalyzes the formation of histone Kbhb on nucleosomes, such as H3K9, H3K18 and H4K8, directly activating downstream transcription [ 33 ]. In HCC, the interaction between metastasis‐associated protein 2 (MTA2) and histone deacetylase 2/chromodomain‐helicase‐DNA‐binding protein 4 (HDAC2/CHD4) inhibits β‐hydroxybutyrate dehydrogenase 1 (BDH1) through R‐loop transcriptional suppression. This inhibition leads to the accumulation of β‐hydroxybutyrate (β‐HB) and an increase in β‐hydroxybutyrylation modification on H3, upregulating stemness‐associated genes linked to poor prognosis in HCC, such as Jumonji domain‐containing 6 ( JMJD6 ), cAMP response element‐binding protein 3 ( CREB3 ), GTP binding protein 4 ( GTPBP4 ), nucleophosmin 1 ( NPM1 ), and translocase of the inner mitochondrial membrane 23 ( TIMM23 ), ultimately promoting HCC formation and progression [ 34 ].

Lactylation, an emerging PTM, has recently gained significant attention for its role in promoting gene transcription and cancer progression through histone modification in various cancer types (Figure 4D )[ 14 ]. For example, in bladder cancer, lactylation of histone H3K18 enhances the expression of the oncogene lipocalin 2 ( LCN2 ), stimulating the proliferation and migration of bladder cancer cells [ 106 ]. Research by Li et al. identified a positive feedback loop involving glycolysis‐H3K18la‐TTK/BUB1B in PDAC, contributing to PDAC development. Augmented glycolysis in PDAC increases lactate production, which elevates H3K18la levels. This lactylation boosts the transcription of two cell cycle‐related genes, TTK and BUB1B . Elevated expression of TTK and BUB1B upregulates the histone lactyltransferase p300, with TTK activating lactate dehydrogenase A (LDHA), further increasing lactate production and promoting histone lactylation, ultimately facilitating PDAC tumor cell proliferation and migration [ 46 ]. In medulloblastoma, histone H3K18 lactylation enhances the promoter activity of genes such as cluster of differentiation 39 ( CD39 ), cluster of differentiation 73 ( CD73 ), and C‐C motif chemokine receptor 8 ( CCR8 ), increasing their expression and creating an immunosuppressive microenvironment within tumors [ 107 ]. Additionally, glucose metabolism regulated by protein kinase R‐like ER kinase (PERK) induces interleukin 10 ( IL‐10 ) expression through histone lactylation, promoting the immunosuppressive function of monocyte‐derived macrophages (MDMs) and advancing glioblastoma progression [ 98 ].

Evidence indicates that histone lactylation upregulates the expression of relevant genes, contributing to tumor drug resistance. In bladder cancer, H3K18 lactylation facilitates the transcription of key target genes Y‐box binding protein 1 ( YBX1 ) and Yin Yang 1 ( YY1 ), enhancing cisplatin resistance [ 102 ]. In CRC, lactate induces the transcription of the rubicon‐like autophagy enhancer ( RUBCNL/Pacer ) via H3K18la, interacts with the autophagy regulatory gene beclin1 ( BECN1 ) to facilitate autophagosome maturation, and mediates the recruitment and function of the class III phosphatidylinositol 3‐kinase complex, thereby reinforcing CRC resistance to bevacizumab treatment [ 36 ]. Elevated lactate levels in CRC also boost the transcription of ATP‐binding cassette transporters like ATP‐binding cassette subfamily C members 2, 3, and 10 (ABCC2/3/10) through histone H4K12 lactylation, resulting in CRC cell insensitivity to irinotecan chemotherapy [ 112 ]. Similarly, in lung cancer, the aldoketoreductase family 1 B10 (AKR1B10) heightens histone H4K12 lactylation through the Warburg effect, stimulates the transcription of cyclin B1 ( CCNB1 ), accelerates DNA replication and the cell cycle, and fosters acquired resistance to pemetrexed in lung cancer brain metastasis patients [ 113 ].

Additionally, glutarylation at histone H4K91 destabilizes nucleosome integrity and perturbs chromatin architecture, thereby inducing global transcriptional activation [ 30 ]. Collectively, these studies systematically elucidate the multidimensional regulatory mechanisms of short‐chain acyl‐PTMs in oncogenic transcriptional programming. Ranging from succinylation‐mediated chromatin structural remodeling to lactylation‐driven drug resistance gene activation, distinct short‐chain modification types orchestrate the epigenetic landscape of tumors through their unique and intricate molecular interaction networks. Notably, post‐translational modifying enzymes such as KAT2A, SIRT5, and p300 emerge as master regulators of tumor progression. In‐depth exploration of these enzymatic targets may unlock novel therapeutic vulnerabilities and precision intervention strategies for cancer treatment.

Short‐chain acyl‐PTMs affect the protein stability of tumor cells

The imbalance of protein homeostasis is a critical factor in tumorigenesis and progression [ 119 ]. Recent studies have revealed that various short‐chain acylation modifications, including lactylation, succinylation, and 2‐hydroxyisobutyrylation, play pivotal roles in regulating tumor protein stability [ 16 , 120 , 121 ]. These modifications exert their effects by influencing protein degradation or stabilization, thereby modulating tumor cell proliferation, metastasis, and drug resistance (Figure 5A and Table 3 ).

Lactylation, a prevalent modification of lysine residues on proteins, inhibits degradation processes, thereby affecting protein stability. For example, in PDAC, lactylation of nuclear and spindle‐associated protein 1 (NUSAP1) at K34 by lactate prevents its degradation, leading to increased NUSAP1 expression. NUSAP1 subsequently enhances LDHA expression by forming a transcriptional regulatory complex with transcription factors c‐MYC and hypoxia‐inducible factor 1‐alpha (HIF‐1α), promoting the Warburg effect and metastasis in PDAC [ 120 ]. Similarly, in cervical cancer, lactylation at K172 on protein Discoidin, CUB, and LCCL domain‐containing type I (DCBLD1) impedes ubiquitin‐mediated degradation, activating the pentose phosphate pathway (PPP) through upregulation of glucose‐6‐phosphate dehydrogenase (G6PD) expression and activity, thereby facilitating cervical cancer cell proliferation and metastasis [ 123 ]. These results suggest that inhibiting protein lactylation associated with tumor progression could serve as a potential therapeutic strategy by hindering tumor cell proliferation and metastasis.

Protein succinylation exerts dual effects on stability, either stabilizing or promoting degradation. In ovarian cancer, carnitine palmitoyltransferase 1A (CPT1A) promotes the succinylation of mitochondrial fission factor (MFF) at K302, hindering Parkin‐mediated ubiquitin‐proteasome degradation of MFF. An accumulation of succinylated MFF then regulates mitochondrial fission and function, enhancing ovarian cancer cell growth and proliferation [ 121 ]. In gastric cancer, fibrillin‐1 (FBN1) is notably upregulated and extensively succinylated at K672, with the succinyl group interfering with its binding to matrix metallopeptidase 2 (MMP2) and impeding its degradation by MMP2, leading to the aberrant accumulation of succinylated FBN1 and its interaction with the transforming growth factor‐β1 (TGF‐β1) complex to activate phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) signaling pathway, promoting tumor cell proliferation and increasing the risk of unfavorable prognosis in gastric cancer patients [ 125 ]. Conversely, for certain proteins, the removal of succinylation proves more beneficial for stability. In hepatic cancer, PRMT5 undergoes desuccinylation at K387 facilitated by SIRT7, preventing its association with E3 ubiquitin ligase STIP1 homology and U‐box containing protein 1 (STUB1), thus reducing ubiquitination and enhancing protein stability, thereby causing the arginine methylation of sterol regulatory‐element binding protein 1a (SREBP1a), which promotes lipid metabolic reprogramming and tumor growth [ 57 ]. In summary, protein stability regulation through succinylation is multifaceted, either stabilizing or facilitating degradation, depending on the specific structures and properties of individual proteins.

Similar to the role of succinylation, the addition of 2‐hydroxyisobutyrylation to lysine residues in proteins exerts a dual regulatory effect on protein stability. For instance, Liao et al. observed that 2‐hydroxyisobutyrylation at lysine 823 on mammalian NAT10, an N4‐acetylcytidine (ac4C) modifying enzyme, enhances its interaction with the deubiquitinase USP39, thereby bolstering NAT10 protein stability. Consequently, NAT10 facilitates esophageal cancer metastasis by upregulating the stability of Notch receptor 3 ( NOTCH3 ) mRNA in an ac4C‐dependent manner [ 16 ]. Conversely, Zhang et al. found that 2‐hydroxyisobutyrylation at lysine 260 on aldehyde dehydrogenase 1 family member A1 (ALDH1A1), a bladder cancer stem cell marker, triggers ALDH1A1 protein degradation through chaperone‐mediated autophagy (CMA), inhibiting bladder cancer tumor growth and increasing sensitivity to chemotherapy drugs. However, HDAC 2/3 mediated removal of 2‐hydroxyisobutyrylation from ALDH1A1 can activate retinoic acid (RA) signaling pathway to promote bladder cancer progression [ 122 ]. This complexity underscores the multifaceted role of 2‐hydroxyisobutyrylation in regulating protein stability in tumor cells, with both major protein degradation pathways in eukaryotic cells influencing the process significantly. While it can impede ubiquitination to stabilize proteins, it can also trigger protein degradation through autophagy. Furthermore, a previous study has elucidated the role of butyrylation in regulating protein stability. In esophageal squamous cell carcinoma (ESCC), syndecan binding protein competitively interacts with HDAC11 for heat shock protein 90 (HSP90) binding, leading to upregulated butyrylation at K754 of HSP90. This modification stabilizes HSP90 protein structure, consequently activating the Akt signaling pathway and inducing 5‐FU chemoresistance in ESCC [ 128 ]. Whether other modifications exhibit similar regulatory mechanisms requires further experimental validation.

In summary, short‐chain acyl‐PTMs, including lactylation, succinylation, 2‐hydroxyisobutyrylation, and butyrylation, dynamically regulate proteostasis, enabling tumor cells to rapidly adapt to metabolic fluctuations and therapeutic stress. These findings unveil novel dimensions for targeted protein degradation strategies. Future integration of proteomic modification profiles may comprehensively decode the “modification code” network governing protein fate determination.

Short‐chain acyl‐PTMs influence the enzyme activity associated with tumor progression

Recent studies have shown that short‐chain acyl‐PTMs, such as succinylation, crotonylation, and lactylation, target key sites in metabolic enzymes, protein kinases, and epigenetic regulatory enzymes. Acting as “molecular switches”, they dynamically modulate enzyme activity, thereby impacting tumor cell metabolic reprogramming and signaling pathways, and driving tumor proliferation, invasion, and drug resistance (Figure 5B and Table 4 ).

Succinylation plays a pivotal role in modulating enzyme activity within metabolic pathways, including glycolysis, bile acid synthesis, and the tricarboxylic acid (TCA) cycle, capable of both enhancing and inhibiting enzyme functions. In invasive prostate cancer cells, SIRT5 levels are significantly reduced compared to early‐stage cells, while succinylation at lysine 118 on LDHA is markedly elevated. The succinylated LDHA‐K118suc, a SIRT5 substrate, significantly boosts LDHA activity, driving lactate accumulation, thereby facilitating the migration and invasion of prostate cancer cells [ 138 ]. In hepatic cancer cells expressing the Yes‐associated protein ( YAP ) oncogene, the absence of SIRT5 increases succinylation levels and the activity of acyl‐CoA oxidase 2 (ACOX2), promoting primary bile acid synthesis such as taurocholic acid, leading to M2‐like macrophage polarization, thus fostering a bile acid‐induced immunosuppressive microenvironment that supports hepatic cancer progression [ 25 ]. Conversely, some enzymes exhibit reduced activity post‐succinylation but increased activity upon desuccinylation. For instance, in hepatic cancer, succinylation at the K284 site of the anti‐cancer protease LACTB, catalyzed by OXCT1, hinders its protease function, resulting in increased phosphatidylserine decarboxylase (PISD) levels in mitochondria. This reduction alleviates LACTB's inhibitory effect on mitochondrial activity, enhancing mitochondrial membrane potential and mitochondrial respiration, thus advancing hepatic cancer progression [ 48 ]. Desuccinylation at malic enzyme 2 (ME2) K346 in CRC activates its enzyme activity, thereby driving CRC progression. Specifically, glutamine deprivation enhances the interaction between SIRT5 and ME2, facilitating SIRT5‐mediated ME2 K346 desuccinylation, which activates ME2 enzyme activity, enhances mitochondrial respiration, counteracts glutamine deficiency, and supports CRC cell proliferation and tumor initiation [ 139 ]. In osteosarcoma, during rapid growth or metabolic stress, SIRT5 catalyzes the desuccinylation of serine hydroxymethyltransferase 2 (SHMT2) at K280, promoting SHMT2 tetramer formation and activating SHMT2 enzyme activity, facilitating serine metabolism and one‐carbon metabolism, ultimately stimulating osteosarcoma cell proliferation [ 140 ]. These results highlight the dual impact of succinylation on enzyme activity regulation, suggesting that targeting succinylation or succinylated metabolic enzymes could present innovative therapeutic strategies for tumors.

The regulatory effects of crotonylation on enzyme activity differ among various enzymes. Previous studies have demonstrated that crotonylation can enhance the activity of key enzymes in the Akt signaling pathway, glycolysis, and other cellular processes, thereby influencing signal transduction and tumor cell metabolism. For instance, in CRC, crotonylation of the protein kinase cAMP‐dependent catalytic‐alpha (PRKACA) at K84 amplifies its kinase activity, leading to the activation of the cyclin E2 (CCNE2) and Paxillin phosphorylation through the protein kinase A (PKA)‐focal adhesion kinase (FAK)‐Akt pathway, thus promoting CRC cell growth, invasion, and migration [ 143 ]. In highly invasive HCC, an increase in the crotonylation level of the GTPase‐active protein Septin2 (SEPT2) is observed, while decrotonylation of SEPT2 at K74 inhibits its GTPase activity. Crotonylated SEPT2 can inhibit the autophagic degradation of P85α and facilitate hepatic cancer cell invasion via the SEPT2‐K74‐P85α‐Akt pathway, with high SEPT2‐K74 crotonylation levels correlating with poor prognosis and higher recurrence rates in HCC patients [ 130 ]. Additionally, a study on cellular metabolism identified a significant increase in the crotonylation of alpha‐enolase (ENO1) in human CRC tissues compared to adjacent tissues. The ENO1 K420cr modification enhances ENO1 activity, increasing lactate production and activating tumor‐associated pathways like the cell cycle, and thereby promoting CRC cell growth, migration, and invasion [ 129 ]. However, it is important to note that crotonylation does not always stimulate enzyme activity. For example, Zheng et al. found that HDAC3‐mediated decrotonylation of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) at the K354 and K553 sites can activate MTHFD1, promoting pancreatic cancer growth and metastasis through NADPH regeneration and increased resistance to ferroptosis [ 131 ]. Therefore, the impact of crotonylation on enzyme activity is complex, and its regulatory role on various metabolic enzymes in tumors is not universally consistent.

Lactylation modification significantly influences various metabolic processes, including lipid metabolism, the pentose phosphate pathway, and the regulation of enzymes essential for RNA N6‐methyladenosine (m 6 A) modification, exerting both stimulatory and inhibitory effects on enzyme activity. For example, in human lung and gastric cancer tissues, the activity of vacuolar protein sorting 34 (VPS34) kinase is elevated due to TIP60‐mediated lactylation at VPS34 protein residues K356/K781, enhancing the binding of VPS34 to Beclin1, autophagy related 14 (ATG14L), and UV radiation resistance‐associated gene protein (UVRAG), thus increasing lipid kinase activity, thereby stimulating cell autophagy and lysosomal degradation [ 133 , 134 ]. In malignant gastric tumors, elevated levels of copper and lactate create a microenvironment that promotes interactions between acyl transferase AARS1/AARS2 and methyltransferase‐like protein 3 (METTL16), leading to increased METTL16 K229 lactylation. This modification elevates enzyme activity, enhances m 6 A modification of ferredoxin 1 ( FDX1 ) mRNA, increases FDX1 mRNA expression, and ultimately induces copper‐mediated cell death in gastric cancer cells [ 51 ]. Conversely, lactylation can also inhibit the activity of certain enzymes, with their function rebounding upon the removal of such modifications. For instance, in hepatitis B virus‐related HCC, lactylation of adenosine kinase 2 (AK2) at K28 impairs its kinase activity, causing energy disorder, downregulating the intrinsic apoptosis pathway, and thereby promoting the proliferation and migration of HCC cells [ 135 ]. Meng et al. found that the HPV16 E6 oncoprotein inhibits lactylation of G6PD at K45 by reducing lactate production, facilitating G6PD dimer formation, increasing enzyme activity, activating the pentose phosphate pathway, and enhancing the proliferation of cervical cancer cells [ 136 ]. Thus, lactylation intricately regulates enzyme activities across various pathways, playing a key role in the pathogenesis and progression of cancers such as gastric, colorectal, and hepatic cancer. Detailed exploration of lactylation modification offers promising avenues for cancer treatment.

In contrast to crotonylation and succinylation, malonylation and 2‐hydroxyisobutyrylation typically inhibit enzyme activity, resulting in enhanced function after deacylation. For example, the removal of malonylation from TKT at K281 in CRC cells boosts enzyme activity, promoting R5P production, maintaining the availability of nucleotides in CRC cells, and thus contributing to CRC cell resistance against 5‐FU [ 56 ]. Additionally, Huang and colleagues identified 1252 Khib modification sites on 346 enzymes in the HeLa cell Khib proteome, including key glycolytic enzymes like phosphoglycerate kinase 1 (PGK1) and ENO1. Notably, unlike the activating impact of crotonylation at ENO1 K420 in CRC [ 129 ], modification at ENO1 K343hib in HeLa cells deactivates the ε‐nitrogen atom and potentially obstructs magnesium ion binding, disrupting the active site residue network and impeding ENO1 functionality [ 132 ].

The aforementioned studies demonstrate that short‐chain acyl‐PTMs, including succinylation, crotonylation, and lactylation, dynamically regulate the activity of tumor metabolic enzymes, protein kinases, and RNA epigenetic regulatory enzymes in a site‐specific and modification type‐dependent manner. These modifications thereby orchestrate tumor cell metabolic processes (e.g., glycolysis, one‐carbon metabolism), signal transduction cascades, and RNA epigenetic regulation, collectively driving tumor metabolic adaptation and malignant progression. Notably, the same modification type (e.g., crotonylation versus 2‐hydroxyisobutyrylation at distinct sites of ENO1) may exert opposing regulatory effects on enzymatic activity depending on specific modification sites or tumor contexts, highlighting the dynamic plasticity of tumor metabolic networks [ 129 , 132 ]. Future investigations should focus on elucidating the precise interaction patterns between these modifications and enzymatic active centers/allosteric regulatory domains, while exploring intervention strategies targeting PTM dynamic equilibrium to advance precision medicine.

Short‐chain acyl‐PTMs affect the nuclear localization of proteins related to tumor progression

In tumor cells, nuclear localization of certain proteins constitutes a critical step for their functional activation. Recent studies have revealed that short‐chain acyl‐PTMs such as succinylation, crotonylation, malonylation, and lactylation, play critical roles in regulating protein nuclear localization by mediating the nuclear translocation of intracellular transcription factors and other functional proteins, thereby influencing gene expression and cellular functionalities, ultimately driving the pathogenesis and progression of various cancers (Figure 5C and Table 5 ) [ 15 , 17 , 29 , 50 , 144 ]. For example, in lung cancer, succinylation at the K7 and K33 sites of transcription factor p23 induces its nuclear translocation, enhancing cyclooxygenase 2 ( COX‐2 ) transcription and tumor growth [ 144 ]. In hepatic cancer, crotonylation at the K265/K270 sites of lamin A aids in maintaining its nuclear localization, preventing cellular senescence, and thus accelerating hepatic cancer cell proliferation [ 15 ]. Additionally, mitochondrial transcription factor A (TFAM) deficiency disrupts the TCA cycle, increasing intracellular malonyl‐CoA levels, which mediate the malonylation of mDia2 at K27 site, facilitating its nuclear translocation, driving actin assembly, increasing the chromatin accessibility of genes such as fibronectin 1 ( FN1 ), transforming growth factor‐β ( TGF‐β ), interleukin 10 ( IL‐6 ), and integrin subunit beta 3 ( ITGB3 ), and inhibiting metastasis of HCC cells. Lactylation modification also plays a significant role in protein nuclear translocation [ 29 ]. In gastric cancer, AARS1 upregulation catalyzes lactylation at the YAP K90 and TEA domain transcription factor 1 (TEAD1) K108 sites within the Hippo signaling pathway, promoting YAP‐TEAD1 nuclear localization and stability, activating target genes like connective tissue growth factor ( CTGF ), cysteine‐rich angiogenic inducer 61 ( CYR61 ), and AARS1 , and stimulating malignant proliferation of gastric cancer cells [ 50 ]. Huang et al. reported that in pancreatic adenocarcinoma, p300 facilitates lactylation of NMNAT1 at K128 site, enhancing its nuclear translocation, preserving enzymatic activity, and supporting the NMNAT1‐dependent NAD + salvage pathway in the nucleus, thus promoting pancreatic cancer cell survival under glucose deficiency [ 17 ].

In summary, these short‐chain acyl‐PTMs exert precise regulation on protein nuclear localization, thereby orchestrating critical oncogenic processes including tumor growth, senescence, and dissemination. Targeting their aberrant intracellular localization may represent a viable strategy to impede tumor progression, reverse therapy resistance, and enhance therapeutic sensitivity through spatial‐functional modulation of cancer‐related proteins.

CROSSTALK OF SHORT‐CHAIN ACYL‐PTMs AND OTHER MODIFICATIONS

Crosstalk between short‐chain acyl‐PTMs and classical PTMs

Most mammalian proteins undergo diverse PTMs. Recent studies have highlighted a substantial increase in the diversity of PTMs, resulting in a significant rise in interactions between short‐chain acyl‐PTMs and classical PTMs (Figure 6A ). These interactions are vital for maintaining genomic stability and gene expression in tumor cells [ 85 , 145 , 146 , 147 ].

H3K9me2 is a well‐established marker for transcriptional repression and is frequently observed as a chromatin alteration during malignant tumor progression [ 145 ]. In ESCC cells, increasing dimethyl succinate (DMS) concentrations elevate pan‐succinylation levels, while H3K9me2, another transcriptional repression marker, correspondingly decreases. This indicates a potential negative regulation of H3K9me2 by succinylation, thereby promoting ESCC metastasis [ 146 ]. Researchers have noted interactions between crotonylation and ubiquitination in resolving replication stress‐induced TRCs and maintaining genomic stability. During replication stress, SIRT1‐mediated H2AK119 deubiquitination is essential for subsequent polycomb complex protein BMI‐1 (BMI1)‐mediated ubiquitination of H2AK119. The accumulation of ubiquitinated H2AK119 at stalled replication forks facilitates RNA polymerase II release and nearby transcriptional repression, ultimately mitigating TRCs, TRC‐related R‐loop formation, and DNA double‐strand breaks [ 85 ]. Furthermore, β‐hydroxybutyrylation of p53 at K120, K319, and K370 leads to reduced acetylation levels, dampening its transcriptional activity and lowering the expression of downstream cell cycle inhibitors p21 and p53 up‐regulated modulator of apoptosis (PUMA), reducing cell growth arrest and apoptosis [ 147 ].

In summary, the crosstalk among various PTMs on the same protein adds complexity to the regulation of protein function, suggesting a delicate balance between these modifications within the intricate metabolic processes of tumor cells. Elucidating the specific mechanisms underlying such balance is essential for advancing tumor therapy.

Crosstalk between short‐chain acyl‐PTMs and RNA modifications

Growing evidence suggests a link between emerging PTMs, particularly lactylation in tumors, and RNA epigenetic changes (Figure 6B ) [ 37 , 51 , 103 , 109 ]. Histone lactylation can elevate the expression of regulatory factors involved in RNA modification, promoting RNA m 6 A or 5‐methylcytosine (m 5 C) methylation. Furthermore, the introduction of lactyl groups to specific sites on RNA modification regulatory enzymes like METTL16, methyltransferase‐like protein 3 (METTL3), and NOP2/Sun RNA methyltransferase family member 2 (NSUN2) can boost their enzymatic activity or RNA‐binding capacity, thereby influencing tumor progression in an m 6 A or m 5 C‐dependent manner.

Research has elucidated the interplay between lactylation modification and RNA m 6 A modification, both contributing to tumor advancement. In gastric cancer, elevated copper and lactate levels prompt the interaction of lactyl transferases AARS1/AARS2 with METTL16, leading to lactylation at K229 and subsequent m 6 A modification of FDX1 mRNA. This cascade increases FDX1 mRNA expression, resulting in copper‐induced cell death in gastric cancer cells [ 51 ]. In CRC, histone H3K18 lactylation induces the upregulation of METTL3 in tumor‐infiltrating myeloid cells (TIMs), promoting m 6 A modification of Jak1 mRNA. Recognition of m 6 A‐modified Jak1 mRNA by the YTH domain‐containing family protein 1 (YTHDF1) enhances Jak1 protein translation and subsequent phosphorylation of STAT3, thereby facilitating immunosuppression of TIMs. Lactylation at key sites K281 and K345 in the zinc finger domain of METTL3 is essential for capturing target RNA [ 37 ]. Additionally, lactylation‐induced upregulation of YTH domain‐containing family protein 2 (YTHDF2) in ocular melanoma identifies m 6 A‐modified period circadian regulator 1 ( PER1 ) and tumor protein p53 ( TP53 ) mRNA, leading to their degradation and contributing to the progression and poor prognosis of ocular melanoma [ 103 ].

Lactylation also influences RNA m 5 C modification. In CRC, the highly expressed m 5 C methyltransferase NSUN2 regulates ENO1 expression in an m 5 C‐dependent manner, enhancing glucose metabolism and lactate production. Accumulated lactate in CRC cells triggers NSUN2 transcription through histone H3K18 lactylation, causing lactylation at Lys356 in the methylation transfer domain (MTD) of NSUN2. This lactylation is essential for capturing target RNA, enhancing RNA‐binding capability, and reprogramming glucose metabolism in an m 5 C‐dependent manner, thereby driving m 5 C‐mediated CRC progression and metastasis [ 109 ].

These findings unveil the connection between short‐chain acyl‐PTMs and RNA epigenetic changes, offering insights into the mechanisms of tumor initiation and progression. They also emphasize the substantial potential of PTM‐regulatory enzymes as targets for drug therapy and diagnostic markers.

TARGETING PTMs FOR CANCER THERAPY

Post‐translational modifications of proteins dynamically regulate protein functions and interaction networks, which are closely associated with the development and progression of various solid tumors. Developing specific inhibitors targeting PTM regulatory enzymes—“Writers”, “Erasers”, and “Readers”—can precisely target the aberrant activation of oncoproteins or inactivation of tumor suppressor proteins, demonstrating significant potential to overcome current therapeutic limitations. Through searching the Zhihuiya New Drug Intelligence Database ( https://synapse.zhihuiya.com/ ) and ClinicalTrials.gov ( https://clinicaltrials.gov ), we identified that inhibitors targeting representative therapeutic targets such as p300/CBP and HDAC family members have entered clinical translation stages for solid tumor therapy (Tables 6 and 7 ). While no clinical studies targeting the “Readers” of PTMs have been reported to date, ongoing advancements in PTM research are expected to yield an increasing number of drugs targeting these modifications to benefit cancer patients.

Clinical trials focusing on “Writers” for solid tumor indications are elaborated in Table 6 . Despite the challenges in developing acetyltransferase inhibitors for clinical use, significant progress has been made with inhibitors targeting the p300/CBP bromodomain [ 177 ]. Current clinical trials mainly emphasize the extensively studied acetyltransferase p300, with certain p300 inhibitors advancing to clinical phases I/II, such as Inobrodib and FT‐7051, for treating hematologic malignancies, prostate cancer, and other conditions. Inobrodib (synonyms: CCS1477) is the pioneering clinical p300/CBP bromodomain inhibitor. In primary acute myeloid leukemia blast cells, CCS1477 impedes cell proliferation by arresting the cell cycle at the G1/S transition and promoting differentiation, as indicated by the elevated expression of CD11b and CD86. Additionally, studies demonstrate that CCS1477 curtails the growth of prostate cancer cell lines, suppresses genes regulated by the androgen receptor (AR) and C‐MYC, and exhibits antitumor efficacy in AR splice variant (AR‐SV) driven models [ 178 ]. Similarly, FT‐7051, an oral and potent p300/CBP inhibitor, shows efficacy in preclinical prostate cancer models, including those resistant to current AR inhibitors like enzalutamide [ 179 ]. Numerous p300 inhibitors are also in early drug discovery and preclinical research. For example, Yang et al. reported that B026 is a selective and orally active p300/CBP inhibitor, which exhibits potent anticancer activity against androgen receptor‐positive (AR+) prostate cancer cell lines, representing a promising clinical development candidate warranting further preclinical investigation [ 150 ]. The emergence of new “Writers” is expected to spur the development of more epigenetic inhibitors, providing novel insights for cancer treatment.

Table 7 details clinical studies targeting “Erasers” in solid tumors. The primary focus is on the HDAC family, which includes pan‐HDAC inhibitors, subtype‐selective inhibitors of HDAC1/2/3/6, pan‐inhibitors for the SIRT family, and SIRT1/2‐specific inhibitors, based on translationally modified therapeutic targets. HDAC inhibitors typically comprise three pharmacophores: the Zn 2+ binding group (ZBG), which chelates with the catalytic Zn 2+ at the active site pocket base; the cap structure (Cap), interacting with the amino acid residues at the HDAC active site entrance; and the linker region connecting the Cap and ZBG regions, targeting the active site's hydrophobic channel [ 180 , 181 ].

Currently, six HDAC inhibitors are available on the market: vorinostat [ 182 ], romidepsin [ 183 ], panobinostat [ 184 ], belinostat [ 185 ], chidamide [ 186 ] and entinostat [ 187 ]. The first four are approved for the treatment of cutaneous T cell lymphoma, peripheral T cell lymphoma, and multiple myeloma, while the latter two are approved for breast cancer therapy. These inhibitors are metal‐dependent, targeting the active site Zn 2+ ion. Vorinostat, belinostat, and panobinostat contain hydroxamic acid groups that chelate Zn 2+ , while romidepsin, a unique bicyclic depsipeptide, features a disulfide bond. Upon cellular entry, this bond in romidepsin is reduced to a thiol, chelating with the Zn 2+ in the catalytic domain center of HDACs, thereby inhibiting their enzymatic activity [ 188 ]. Due to their lack of specificity for a particular HDAC isoenzyme, these inhibitors may cause off‐target effects such as nausea, vomiting, fatigue, and cardiotoxicity, limiting their clinical use [ 189 ]. Consequently, the design of selective inhibitors for specific HDAC isoenzymes remains a key objective in current drug development. Chidamide stands out as China's first independently developed epigenetic regulatory drug and the world's primary orally administered subtype‐selective HDAC inhibitor. It primarily targets Class I HDAC1, 2, 3, and Class IIb HDAC10, modulating epigenetic alterations in hematological tumors and solid tumors, including breast cancer. Approved for the treatment of peripheral T cell lymphoma and breast cancer, chidamide marks a significant advancement from hematologic malignancies to solid tumors. Recent preclinical studies highlight its potent anti‐tumor and synergistic effects in solid tumors such as bladder cancer, paving the way for clinical trials in various malignancies [ 190 ]. At the 2023 American Society of Clinical Oncology (ASCO) meeting, four clinical studies on chidamide in NSCLC, breast cancer, soft tissue sarcoma, and urothelial cancer were presented, showing promise for improved patient outcomes. Furthermore, ongoing clinical trials are investigating the efficacy of HDAC inhibitors in combination with other inhibitors targeting entities like lysine‐specific histone demethylase 1A (KDM1A) and the PI3K family.

Research on PTMs and their sites has intensified, leading to the development of several prediction websites, including the PTMD database ( https://ptmd.biocuckoo.org/ ) [ 191 ], DbPTM ( https://awi.cuhk.edu.cn/dbPTM/ ) [ 192 ], and FSL‐Kla ( http://kla.zbiolab.cn/ ) [ 193 ], which provides robust support for the discovery of drug targets associated with PTMs and the investigation of their functional mechanisms. For example, the PTMD database catalogs 342,624 disease‐related PTM events in 15,105 proteins linked to 93 types of PTM and 2,083 diseases, providing insights into known protein PTM sites and protein‐protein interactions (PPI) [ 191 ]. PTMD is a key resource for understanding the relationship between PTMs and diseases and enhancing knowledge of disease progression, diagnosis, and therapeutic interventions. Jiang et al. identified 343 distinct lactylation sites in 191 proteins across three species, introducing the novel predictor “FSL‐Kla” to assist researchers in identifying potential lactylation modification sites. Furthermore, DbPTM integrates experimentally verified PTMs from various databases, annotating potential PTMs for all UniProtKB protein entries, a service maintained for over a decade. This database serves as a comprehensive repository for functional and structural analyses of PTM sites, providing details on cell line origins, multi‐omics data (transcriptome, proteome, single nucleotide variations, copy numbers), RNA perturbations (RNAi/CRISPR), and cellular responses to pharmaceutical agents. The enhanced DbPTM consolidates experimentally verified PTMs from existing resources and curated literature and also disseminates disease associations based on non‐synonymous single nucleotide polymorphisms (nsSNPs). In conclusion, the development and continuous refinement of PTM‐related databases hold significant importance for in‐depth investigations into the functional mechanisms of PTMs and the discovery of associated drug targets. Future research should focus on systematically mining these resources to develop more inhibitors targeting diverse PTM types, thereby overcoming the off‐target effects of current therapies and providing more effective treatment strategies for cancer patients.

SUMMARY AND FUTURE PERSPECTIVES

In recent years, advancements in mass spectrometry‐based proteomics and PTMs‐specific antibody technologies have facilitated the discovery of numerous novel histone and non‐histone modifications [ 2 ]. This review focuses on eight short‐chain acyl‐PTMs —butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2‐hydroxyisobutyrylation, β‐hydroxybutyrylation, and lactylation. It comprehensively summarizes their discovery history, regulatory enzyme systems, multi‐dimensional regulatory mechanisms mediating tumor progression, and clinical research advances in targeting regulatory enzymes. The work not only provides crucial references for subsequent in‐depth exploration of PTMs' functional networks in tumor progression, but also lays a theoretical foundation for developing novel therapeutic strategies targeting PTM regulatory enzymes.

The exploration of common solid tumors highlights extensive research on succinylation, crotonylation, and lactylation, with a particular focus on lactylation in recent years within epigenetic regulation. These modifications dynamically regulate genomic stability, gene transcription, protein stability, enzymatic activity, nuclear localization, and interaction networks, profoundly participating in core processes such as tumor metabolic reprogramming and immune evasion. For example, histone H3K18 crotonylation and lactylation enhance chromatin accessibility to promote oncogene transcription, while short‐chain acylation modifications of non‐histone substrates drive tumor progression by altering protein stability, enzymatic activity, or nuclear localization. Notably, a single protein may be regulated by multiple PTMs, resulting in distinct functional outcomes. For instance, the p53 protein undergoes succinylation, crotonylation, and β‐hydroxybutyrylation: desuccinylation at K120 suppresses its transcriptional activity [ 55 ]; crotonylation at serine 46 reduces p53 protein levels [ 47 ]; and β‐hydroxybutyrylation at K120/319/370 decreases its acetylation levels, thereby weakening transcriptional activity [ 147 ]. Intriguingly, a multidimensional interaction network exists between short‐chain acyl‐PTMs and RNA epigenetic modifications such as m 6 A and m 5 C. For example, lactylation can upregulate the expression of RNA modification regulators by modifying histones or directly modify related regulatory factors to alter their activity, thereby governing tumor initiation and progression through m 6 A‐ or m 5 C‐dependent mechanisms [ 37 , 51 , 103 , 109 ]. This cross‐epigenetic‐layer interplay provides novel perspectives for deciphering the mechanisms of tumor epigenetic regulation.

Although significant progress has been made in understanding the role of short‐chain acylation modifications in tumorigenesis, critical gaps and challenges persist. These include: (1) incomplete characterization of regulatory enzyme systems for short‐chain acylation modifications such as butyrylation, malonylation, and glutarylation; (2) inadequate targeting activity and design specificity of enzyme inhibitors; (3) unresolved integration strategies combining these inhibitors with conventional therapies; (4) technical barriers in achieving tumor‐specific drug localization [ 194 ]. For instance, the precise regulatory mechanisms underlying these modifications in tumor progression remain largely elusive, necessitating the integration of multi‐omics approaches (spatial proteomics, metabolomics, and genomics) to fully decipher their regulatory networks. Furthermore, the shared utilization of core regulatory enzymes (e.g., p300/CBP and HDACs) across different acylation types highlights an urgent need to elucidate their dynamic equilibrium mechanisms. Significantly, current therapeutic strategies focus predominantly on targeting PTM‐related “Writers” and “Erasers”, whereas interventions directed at “Readers” remain largely unexplored. In addition, existing “Erasers” inhibitors, mainly pan‐HDAC inhibitors, suffer from limited subtype selectivity and off‐target effects, highlighting the critical need to develop HDAC inhibitors with enhanced specificity and reduced toxicity to mitigate adverse outcomes.

Collectively, while the pivotal role of short‐chain acyl‐PTMs in tumor biology has been well established, their clinical translation remains hindered by multifaceted challenges. Current evidence positions lactylation modification as a promising therapeutic frontier with distinct clinical advantages. Specifically, metabolic heterogeneity, a unique dimension of tumor heterogeneity distinct from genetic/epigenetic variations, manifests through tumor cells' reliance on aerobic glycolysis (Warburg effect) [ 195 ]. This metabolic reprogramming generates excessive lactate, creating an acidic tumor microenvironment (pH 6.5‐7.0) that drives malignant progression via immune suppression, metastatic potential, and therapy resistance [ 196 ]. As a lactate‐derived epigenetic modification, lactylation serves as a crucial bridge connecting metabolic heterogeneity with epigenetic regulation, demonstrating tremendous potential in three key areas: diagnostic biomarker development, targeted therapy design, and remodeling the immunosuppressive microenvironment. However, clinical implementation of lactylation‐based strategies faces multiple challenges, such as incomplete mechanistic understanding of its dynamic regulation, technical limitations in detection sensitivity, and insufficient individualized treatment strategies. Therefore, developing highly sensitive lactylation detection tools is crucial for precise diagnosis and treatment. Additionally, combination therapies based on metabolic heterogeneity can be designed targeting the lactate metabolism in the tumor microenvironment. Furthermore, exploring the interactions between lactylation modification and other epigenetic modifications is also of great significance. Through interdisciplinary innovation integrating metabolomics, epigenetics, and systems biology, lactylation modification may emerge as a next‐generation precision oncology target capable of overcoming current therapeutic bottlenecks.

In summary, future research on PTMs should prioritize the identification of regulatory enzymes and modification sites in short‐chain acylation, as well as the characterization and analysis of dynamic substrates under diverse physiological and pathological conditions. A deeper understanding of the regulatory mechanisms by which short‐chain acylation modifications influence tumor progression, exploration of synergistic or antagonistic relationships among modifications, and enhanced investigation into the link between these modifications and tumor drug resistance will offer novel therapeutic targets and theoretical foundations for cancer treatment.

AUTHOR CONTRIBUTIONS

Huizhe Wu, Ting Wu, and Yingqi Zhao conceived the manuscript. Ting Wu and Yingqi Zhao investigated the literature, drafted the manuscript and generated the figures. Xin Zhang, Yuanhe Wang and Qiuchen Chen contributed to the literature collection and created the tables. Mingrong Zhang and Huan Sheng contributed to the literature collection and the creation of the figures. Yuying Zhang, Jinyu Guo and Jun Li contributed to the creation of the tables. Yuxuan Fan, Ziqing Wang, Yalun Li, and Haoran Wang contributed to the literature collection. Minjie Wei supervised the findings of this work and completed the final manuscript. Xiaoyun Hu supervised the findings of this work, corrected the figures and completed the final manuscript. Huizhe Wu supervised the findings of this work, offered crucial content revision and completed the final manuscript. All authors contributed actively to the manuscript and approved the final version.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

ACKNOWLEDGMENTS

We thank the Bullet Edits Limited for the linguistic editing and proofreading of the manuscript. This work was supported by grants from the National Natural Science Foundation of China (82272915), Science and Technology Innovation Team Project of China Medical University (CXTD2022007), Beijing Xisike Clinical Oncology Research Foundation (Y‐Gilead2024‐PT‐0201), China Postdoctoral Science Foundation (2023MD734246, 2025T180577), Liaoning Province Natural Science Foundation Joint Fund (2023‐MSLH‐396), and Doctoral Start‐up Foundation of Liaoning Province (2024‐BS‐066).

Wu T, Zhao Y, Zhang X, Wang Y, Chen Q, Zhang M, et al. Short‐chain acyl post‐translational modifications in cancers: Mechanisms, roles, and therapeutic implications. Cancer Commun. 2025;45:1247–1284. 10.1002/cac2.70048

Ting Wu, Yingqi Zhao, Xin Zhang, Yuanhe Wang, and Qiuchen Chen contributed equally to this work.

Contributor Information

Minjie Wei, Email: mjwei@cmu.edu.cn.

Xiaoyun Hu, Email: huxy2022@cmu.edu.cn.

Huizhe Wu, Email: wuhz@cmu.edu.cn.

DATA AVAILABILITY STATEMENT

Not applicable.

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Associated Data

Data Availability Statement

Not applicable.