Post-translational modifications of integrins: molecular mechanisms and pathological implications

Abstract

Integrins are cell-surface adhesion receptors that mediate bidirectional signaling governing migration, proliferation, and survival. Emerging evidence reveals that integrin function is finely controlled by an interconnected network of post-translational modifications (PTMs), spanning classical modifications such as glycosylation and phosphorylation, as well as novel metabolite-driven alterations including carbamoylation and cysteine carboxyethylation. These PTMs collectively orchestrate integrin stability, conformation, trafficking, and downstream signaling, with profound implications for tumor progression, metastasis, fibrosis, and therapy resistance. We further highlight critical cross‑talk among distinct modification types and demonstrate how environmental cues (e.g., metabolic byproducts, gut microbiota metabolites) directly modify integrins. Finally, we explore emerging therapeutic strategies inspired by these insights, including targeted enzyme inhibitors, proteolysis targeting chimeras (PROTACs), deubiquitinase-targeting chimeras (DUBTACs), and PTM-editing tools such as dCasRx-based m6A editors. Deciphering the integrin PTM code transforms our understanding of cell adhesion biology and opens new frontiers for diagnostic biomarkers and precision therapy.

Introduction

Integrins are a major family of cell surface adhesion receptors that mediate two-way signal transduction between cells and the extracellular matrix [1]. Discovered in the 1980 s, integrins are now central regulators of cell migration, proliferation, differentiation, and survival. Their discovery was retrospectively honored with the 2022 Lasker Basic Medical Research Award [2]. Beyond development and homeostasis, dysregulated integrin function drives cancer metastasis, fibrosis, thrombosis, and cardiovascular disease [3, 4]. Thus, precise control of integrin activity is crucial for physiological integrity, and its disruption represents a core driver of human disease.

For decades, integrin research focused on transcriptional regulation, subunit composition, and ligand affinity [1, 5]. This framework revealed how expression levels dictate adhesive capabilities [1]. However, it has become clear that this view is incomplete. Post-translational modifications (PTMs) provide an additional, dynamic layer of regulation that governs the integrin life cycle, from biosynthesis and folding to membrane localization, activation, and degradation [6]. PTMs covalently attach functional groups to proteins or cleave peptide bonds, expanding proteomic diversity without altering DNA sequence [7]. Over 650 PTM types have been identified, including phosphorylation, glycosylation, ubiquitination, methylation, acetylation, and nitrosylation, each modulating protein folding, conformation, stability, localization, and interactions [8]. Early studies on integrin N-glycosylation established a precedent for PTM regulation in this family. Recent advances in mass spectrometry have enabled discovery of novel modifications, such as succinylation, lactylation, and crotonylation, revealing their widespread roles in physiology and disease [9]. PTMs thus represent a crucial epigenetic and epi-transcriptomic layer that fine-tunes protein function in response to cellular cues.

Despite decades of PTM research, a systematic understanding of how these modifications collectively orchestrate integrin biology remains fragmented. Isolated PTM events on integrin subunits have been reported, but a comprehensive synthesis integrating these findings into a coherent PTM code is lacking. Critically, these modifications do not act in isolation. They form an intricate network where phosphorylation influences ubiquitination [10], glycosylation modulates conformation and ligand binding [11], and RNA methylation controls protein expression [12]. This landscape is further expanded by emerging metabolite-driven modifications, including carbamylation in chronic kidney disease [13] and citrullination in inflammatory disorders [14]. This interplay determines integrin function in a context-dependent manner, and its dysregulation drives diseases from metastatic cancer to fibrosis and autoimmunity [3]. In this review, we provide an integrated overview of the integrin PTM landscape, exploring mechanisms by which glycosylation, phosphorylation, ubiquitination, methylation, acetylation, nitrosylation, carbamoylation and cysteine carboxyethylation regulate integrin stability, conformation, trafficking, and signaling. By mapping modifications onto specific subunits and linking them to pathological states, we highlight how decoding this integrin PTM code reveals fundamental insights into cell adhesion biology and uncovers diagnostic biomarkers and therapeutic targets for human disease.

Structure and signal transduction of integrins

Integrins are heterodimers composed of a non-covalently linked α-subunit (120–185 kD) and a β-subunit (90–110 kD). Each subunit includes the large extracellular head, the leg domains, the single-pass transmembrane helix, and the short cytoplasmic tail [1]. At least 24 integrin macromolecules with different functions have been found in mammals, which are composed of 18 α subunits (α1 ~ 11, αⅡb, αD, αE, αL, αM, αV, αX) and 8 β subunits (β1–8) [15]. Each integrin and its dimer have a specific and non-redundant function, thus having different substrate specificity. Multiple α chains can bind to the same β chain, and vice versa. The integrin β1 forms the largest subgroup of integrins because the β1 subunit can form heterodimers with the largest number of α subunits (at least 12) [1]. The binding mechanisms of integrins are diverse; a cell or extracellular matrix can bind to several different integrins, and a single integrin can bind to several different extracellular matrices (Fig. 1).

Fig. 1.

Structure and signal transduction of integrins

Integrins are unique in their ability to transmit biological signals through two pathways across the plasma membrane: via interactions with intracellular proteins and extracellular domains [5]. So far, a variety of integrin interacting proteins in extracellular and cytoplasmic domain have been found, which are involved in many aspects of biological functions. Generally, integrins bind to ligands by recognizing the arginine glycine aspartate (RGD) or leucine aspartate valine (LDV) sequences [16]. Outside cells, integrins interact with various ligands, including cell receptors, extracellular matrix proteins, soluble proteins in body fluids, microbial proteins, and carbohydrates. Different integrin dimers exhibit distinct ligand-binding preferences [5]. For instance, many integrin dimers of integrin β1, such as α5β1, bind to extracellular matrix proteins such as fibronectin, while α1β1, α2β1, α10β1 bind to different types of collagen. Furthermore, certain integrin dimers, such as integrin α4β1, α9β1, and α4β7, can bind to cell ligands including intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecule-1 (VCAM-1) [17]. The signals from inside to outside and from outside to inside are related to the obvious conformational changes of the extracellular domain of integrins. These changes vary with cell type, ligand state and properties [5]. In resting cells, integrins remain inactive with their heads folded and curved. The cytoplasmic portions of α and β subunits are interconnected and mutually constrained, thereby stabilizing the curved conformation [18]. Intracellular regulatory proteins (e.g., Talin, Kindlin) bind to the cytoplasmic domains of integrins, activating them and inducing conformational changes that favor ligand binding [19]. Upon activation, integrins exhibit enhanced extracellular domain affinity for extracellular ligands (e.g., collagen, fibronectin, and other extracellular matrix components). This binding facilitates the formation of intracellular protein complexes, subsequently activating multiple signaling pathways including FAK and Src. The affinity of integrins to the extracellular matrix (ECM) and the downstream events mediated by integrins are regulated by the dynamic equilibrium between these conformations [20].

Physiological and pathological functions of integrins

Integrins constitute a major family of cell surface adhesion receptors that mediate dynamic bidirectional signaling across the plasma membrane, governing a broad spectrum of cellular processes including adhesion, migration, proliferation, differentiation, and survival [1, 5]. Their functional repertoire extends across both physiological and pathological contexts. During embryonic development, integrins are indispensable for implantation, morphogenesis, and tissue organization; in adult tissues, they maintain homeostasis through cell–ECM interactions that regulate tissue architecture and turnover. Pathologically, aberrant integrin signaling drives a diverse array of human diseases, ranging from tissue fibrosis and immune inflammatory disorders to cardiovascular diseases and cancer metastasis [3].

The functional versatility of integrins is exemplified by their interactions with intracellular adapter proteins that translate extracellular engagement into intracellular signals. Kindlin proteins, for instance, bind to the cytoplasmic tail of β-integrins and orchestrate directed cell migration, proliferation, differentiation, and survival [21]. More strikingly, viral pathogens have evolved to exploit this signaling machinery: the hepatitis B virus protein X (HBx) induces proteasomal degradation of talin-1—a key integrin-activating adapter—to relieve viral restriction and sustain HBV replication, illustrating how integrin signaling can be hijacked in infectious disease [22].

In cancer, integrin signaling undergoes profound reprogramming that fundamentally alters tumor cell behavior. Integrins promote tumor progression through multiple convergent mechanisms—facilitating metastasis, enhancing tumor invasiveness, driving tumor-induced angiogenesis and lymphangiogenesis, and fostering connective tissue proliferation and inflammation [3]. Genetic evidence from transgenic mouse models has directly demonstrated the causal role of integrins in tumorigenesis: targeted disruption of integrin β1 in the mammary epithelium suppresses both the initiation and maintenance of mammary tumor growth in vivo [4]. Beyond the cancer cell itself, epigenetic regulation of integrin and integrin-linked kinase gene expression is intimately linked to carcinogenesis and the maintenance of cancer stem cells [3, 4]. Consistent with these mechanistic insights, integrins are aberrantly overexpressed across diverse tumor types, where they promote tumor cell invasiveness and activate multiple downstream signaling pathways that collectively shape the malignant phenotype [3, 22].

Transcriptional regulation of integrin expression has been extensively studied [1, 3, 4]. However, it is increasingly clear that the rapid and reversible control required for dynamic cellular processes is achieved primarily through PTMs. Examples of such processes include immune cell trafficking, cancer cell invasion, and platelet activation [7]. PTMs fine-tune integrin conformation, stability, membrane trafficking, and signaling complex assembly in response to extracellular cues, adding a layer of regulatory complexity that cannot be explained by gene expression alone. Understanding this PTM-based regulatory layer is therefore essential for deciphering integrin function in health and disease and for identifying novel therapeutic targets.

Post-translational modifications of integrin and their function in diseases

Beyond transcriptional regulation, integrin function is dynamically controlled by a diverse array of PTMs that occur throughout the protein lifecycle [7]. These modifications, including glycosylation, phosphorylation, ubiquitination, methylation, acetylation, nitrosylation, and others, fine-tune integrin conformation, stability, trafficking, and signaling complex assembly in response to cellular and environmental cues (Fig. 2). In the following sections, we systematically review each major class of integrin PTM, discussing their molecular mechanisms, effects on integrin function, and emerging roles in specific disease contexts (Table 1). By systematically correlating specific PTM events on distinct integrin subunits with their associated pathological states, we demonstrate that deciphering this integrin PTM code not only advances our fundamental understanding of cell adhesion biology but also paves the way for the identification of novel diagnostic biomarkers and actionable therapeutic targets.

Fig. 2.

Post-translational modifications (PTMs) identified in integrin subunits

Table 1.

Post-translational modifications and a few epigenetic modifications of integrins: subunit specificity and disease associations

Modification type	Integrin subunit	Core function	Associated diseases
Glycosylation	αV, α5, β1	Only the O-glycosylation of αV enhances FAK signaling and drives invasion	Pancreatic ductal adenocarcinoma [23]
	β3	Promotes viral internalization (O-glycosylation); inhibits viral entry (N-glycosylation)	Human cytomegalovirus infection [24]
	β1	Regulates folding and membrane localization	Syndromic macrothrombocytopenia [25]
	αV	Enhances binding to Galectin-3, stabilizes integrin	Prostate cancer [26]
	β1	Activates FAK phosphorylation, promotes adhesion and migration	Cancer [27]
	β1	Blocks FAK/AKT pathway, suppresses metastasis	Breast cancer [11]
	α5	Enhances stability, inhibits ubiquitination-mediated degradation	Glioblastoma [28]
	α6, β1	Promotes binding to laminin	Hepatocellular carcinoma [29]
	αV	Enhances binding to uPAR	Glioblastoma [30]
	α2	Enhances adhesion function and cell survival	Ovarian cancer [31]
	α2, β1	Promotes cell adhesion	Primary myelofibrosis [32]
	αVβ3	Enhances integrin activity	Breast cancer [33]
	β1	Mediates sEV internalization, promotes metastasis	Bladder cancer [34]
	αM	Inhibits T cell function	Cancer [35]
Phosphorylation	β1	Inhibits kindlin-2 binding, negatively regulates activation	Cancer [36]
	β1	Promotes invasive pseudopodia formation	Breast cancer [10]
	β1	Drives osteoblast-like differentiation	Vascular calcification [37]
	β3	Promotes colorectal cancer progression	Colorectal cancer [38]
	β4	Inhibiting phosphorylation delays vascular aging	Vascular aging [39]
	β4	Function to be determined	Cancer [40]
	β5	Y766 phosphorylation regulates curved adhesions formation	Cancer [41]
Ubiquitination	α5	Induces degradation, promotes apoptosis	FGFR2-related bone disease [42]
	β1	CUL5 deficiency inhibits degradation, promotes metastasis	Small cell lung cancer [43]
	β1	Induces degradation, leads to cardiomyocyte apoptosis	Dilated cardiomyopathy [44]
	β1	Inhibits ubiquitination, protects blood-brain barrier	Subarachnoid hemorrhage [45]
	β1, β5	Deubiquitination stabilizes integrins, promotes fibrosis	Fibrotic disease [46]
	β1	Deubiquitination maintains surface integrin pool	[47]
	β4	Induces degradation, suppresses tumor progression	Esophageal cancer [48]
Methylation	α1, α4, α9	Promoter hypermethylation silences gene expression	Breast cancer [49]
	α10	Promoter methylation exacerbates lung injury	Sepsis-related diseases [50]
	β7	DNA hypomethylation enhances expression	Multiple myeloma [51]
	β6, αM	H3K4me3 activates transcription	Ovarian cancer [52]
	αV	DNA methylation and m6A regulate expression	Gastric carcinoma [53]
	β1	m6A modification regulates mRNA stability	Diabetic retinopathy [12]
	β1	METTL3 downregulation impairs T cell infiltration	Solid tumor [54]
	α6	m6A demethylation inhibits tumor progression	Bladder cancer [55]
	β1	m6A modification promotes bone metastasis	Prostate cancer [56]
	α4	m6A modification accelerates degradation, inhibits metastasis	Renal clear cell carcinoma [57]
	α4	m6A modification promotes drug resistance	Acute myeloid leukemia [58]
	α4	Protein methylation inhibits fibrosis	Hepatic fibrosis [59]
	β2	Promoter methylation suppresses expression, alleviates myocardial injury	Myocardial infarction [60]
Acetylation	β1	Enhances kindlin-2 binding, promotes angiogenesis	Cancer [61]
	β3	SIRT2-mediated deacetylation weakens adhesion, promotes metastasis	Lung cancer [62]
	β3	mRNA acetylation promotes osteosarcoma progression	Osteosarcoma [63]
	α7β1	Alters histone modification states	Intestinal tumor [64]
Nitrosylation	β1	Inhibits ubiquitination, enhances inflammatory adhesion	Cardiovascular disease [65]
	αIIbβ3	Inhibits platelet aggregation	Thrombotic diseases [66]
	α6	Enhances β1 association, promotes migration	Prostate cancer [64]
	β3	Maintains filtration barrier integrity	Diabetic nephropathy [67]
	α8	Inhibits gene expression, suppresses calcification	Aortic valve calcification [68]
Carbamylation	αIIbβ3	Conformational change inhibits platelet function	End-stage renal disease [13]
Cysteine carboxyethylation	αIIb	The activation of CD4 + T cells by CBS catalyzing the carboxylation of cysteine at Cys96 site induces autoimmune disease.	Ankylosing spondylitis [69]

Glycosylation: the sugar code for integrin recognition and signaling

Glycosylation represents one of the most abundant and structurally diverse PTMs on integrins. It encompasses N-linked glycosylation on asparagine residues, O-linked glycosylation on serine or threonine residues, and sialylation, which is the terminal addition of sialic acids. This modification coats integrins with a complex sugar code that influences every stage of their lifecycle, from folding and trafficking to membrane localization, ligand binding, and turnover [27, 28]. Glycosyltransferases such as MGAT5, B4GALT1, and C1GALT1 install specific glycan structures at defined residues, generating a repertoire of glycoforms that dictate integrin function in a context-dependent manner [29]. A well-established paradigm is the antagonistic regulation by different N-glycan branching patterns: MGAT5-catalyzed β1,6-branched glycosylation promotes integrin αV clustering with galectin-3, enhancing downstream signaling and driving prostate cancer progression, whereas MGAT3-introduced bisecting GlcNAc inhibits this interaction and suppresses breast cancer metastasis [11, 26]. This opposing relationship illustrates how subtle glycan changes can profoundly alter integrin-mediated signaling (Fig. 3).

Fig. 3.

The antagonistic regulation of glycosylation

Beyond signaling regulation, glycosylation dictates integrin stability and immune interactions. In glioblastoma, B4GALT1-mediated N-glycosylation stabilizes ITGA5 by shielding it from ubiquitination, activating FAK/RUNX1 signaling and promoting T cell dysfunction [28]. Sialylation modulates cell adhesion by altering the net negative charge on the cell surface, which can affect electrostatic interactions with the ECM, and by directly influencing the conformation of the ligand-binding pocket of integrin [35]. More intriguingly, specific sialoglycan variants on integrins serve as recognition signals for small extracellular vesicles, directing organotropic metastasis by facilitating recipient cell internalization [27, 34]. Sialylated integrin αM on myeloid cells is also recognized by the immune checkpoint Siglec-15, revealing a direct link between integrin glycosylation and tumor immune evasion [35].

The clinical relevance of integrin glycosylation spans multiple diseases. High C1GALT1 expression enhances integrin αV O-glycosylation in pancreatic cancer, activating FAK signaling and correlating with poor prognosis [23]. In cytomegalovirus infection, integrin β3 O-glycosylation at Ser85 promotes viral entry, while N-glycosylation at Asn125 exerts opposing effects. This demonstrates site-specific functional divergence [24, 70]. These insights are informing therapeutic development: inhibiting glycosyltransferases such as MGAT5 blocks tumor metastasis in preclinical models [26], while integrin glycoforms on circulating vesicles are emerging as liquid biopsy biomarkers for cancer diagnosis [27, 34]. The intersection of glycosylation with immune checkpoint regulation further suggests that glycan-based strategies could synergize with existing immunotherapies. For instance, antibodies or small molecules that block the synthesis of specific sialoglycans on integrin αM could disrupt the Siglec-15 immune checkpoint, potentially reactivating T cell anti-tumor responses [35].

Phosphorylation: the dynamic switch of integrin activation and signaling

Phosphorylation represents a central and rapidly reversible post-translational modification that governs integrin function primarily through modification of specific serine, threonine, or tyrosine residues within the intracellular domain of the β subunit [16, 71]. This modification acts as a dynamic molecular switch, enabling precise spatiotemporal control of integrin activation, downstream signaling, and cytoskeletal coupling in response to cellular cues. The phosphorylation status of integrins is tightly regulated by the opposing actions of protein kinases such as Src and FAK, and phosphatases including PTP-PEST, Shp2, and PPM1F [2, 9, 10].

A well-characterized paradigm is the phosphorylation of the NPxY motif in the integrin β1 cytoplasmic tail. Src kinase-mediated phosphorylation at Tyr783 recruits adaptor proteins including Dok1 and Cofilin, promoting invasive pseudopodia formation and enhancing breast cancer cell migration and metastasis [10]. A recent study using a FRET-based biosensor identified Shp2 and PTP-PEST as negative regulators of this phosphorylation event, demonstrating that dynamic modulation of NPxY site phosphorylation is critical for efficient cancer cell invasion [10]. Conversely, phosphorylation at the adjacent T788/T789 motif exerts an opposing effect by inhibiting integrin binding to the key activator kindlin-2, thereby negatively regulating integrin activation and cell adhesion, challenging earlier assumptions about the uniform activating role of integrin phosphorylation [36] (Fig. 4). The functional consequences extend beyond β1: in vascular endothelium, FLRT2-mediated inhibition of integrin β4 Tyr1510 phosphorylation activates the mTORC2-AKT-p53 pathway, delaying endothelial cell senescence and vascular aging [39]; in colorectal cancer, ANGPTL3-induced phosphorylation of integrin β3 at Tyr773 promotes tumor progression [38].

Fig. 4.

Site-specific phosphorylation of integrin β1 cytoplasmic tails

Dysregulated phosphorylation underlies diverse pathologies including cancer invasion, vascular aging, and immune dysfunction, with the latter exemplified by defective integrin β2 phosphorylation in leukocyte adhesion deficiency syndrome [71]. These mechanistic insights are opening new therapeutic avenues. The identification of PPM1F as the phosphatase that dephosphorylates the integrin β1 T788/T789 motif has led to the development of Lockdown, a selective small-molecule PPM1F inhibitor that blocks cancer cell invasion by maintaining integrin in a hyper-adhesive state [36]. Similarly, targeting Src kinase or phosphatases such as Shp2 in tumors with elevated NPxY site phosphorylation represents a promising precision therapy strategy [10]. The context-dependent and site-specific nature of integrin phosphorylation underscores the need for highly specific phosphorylation-state antibodies and biosensors for both diagnostic applications and therapeutic monitoring [71].

Ubiquitination: the arbiter of integrin stability and surface abundance

Ubiquitination serves as a primary determinant of integrin protein stability and surface availability, governing the delicate balance between integrin degradation and recycling [43]. This modification is orchestrated by the opposing actions of E3 ubiquitin ligases that covalently attach ubiquitin chains to target integrins, marking them for proteasomal or lysosomal degradation, and deubiquitinases (DUBs) that remove these tags to stabilize integrin proteins [46, 47]. The ubiquitination status of integrins dynamically regulates their half-life and membrane localization, thereby controlling the duration and intensity of integrin-mediated signaling.

The functional consequences of integrin ubiquitination are exemplified by the opposing regulation of integrin stability in different pathological contexts. FGFR2 activation recruits the E3 ligase Cbl to trigger K63-linked ubiquitination and proteasomal degradation of integrin α5, leading to osteoblast detachment and apoptosis [42]. Conversely, CUL5 deficiency inhibits K11-linked ubiquitination of integrin β1, stabilizing the protein and activating FAK/SRC signaling to promote small cell lung cancer metastasis [43]. On the deubiquitination side, USP10 removes ubiquitin from integrins β1 and β5, stabilizing them and activating TGF-β signaling to drive fibrotic wound healing [46]. The USP12/46-WDR48-WDR20 complex similarly removes ubiquitin from internalized integrin β1 in early endosomes, preventing ESCRT-mediated lysosomal degradation and maintaining surface integrin pools [47] (Fig. 5).

Fig. 5.

Ubiquitination and deubiquitination balance integrin stability

Dysregulated ubiquitination contributes to diverse pathologies including cancer metastasis, fibrosis, dilated cardiomyopathy, and blood-brain barrier disruption after subarachnoid hemorrhage [44, 45]. These mechanistic insights are informing therapeutic strategies. In CUL5-deficient small cell lung cancer, the elevated integrin β1 stability confers sensitivity to SRC inhibitors such as dasatinib, exemplifying a precision therapy approach guided by PTM status [43]. Targeting deubiquitinases like USP10 with selective inhibitors represents a promising strategy for fibrotic diseases [46]. The recognition that specific E3 ligase signatures define integrin stability in different contexts opens new avenues for biomarker development and targeted intervention.

Methylation: a multi-level epigenetic regulator of integrin expression

Methylation represents a uniquely versatile modification that regulates integrin function at multiple interconnected levels, including epigenetic modifications ranging from DNA and histone methylation in the nucleus to RNA methylation in the cytoplasm, and PTMs on integrin molecules [12, 49, 59]. This review focuses primarily on PTMs, but we briefly discuss DNA/RNA methylation where relevant to illustrate how different regulatory layers converge on integrin function.

RNA methylation, particularly N6-methyladenosine (m6A) modification, has emerged as a critical regulator of integrin expression at the post-transcriptional level. The methyltransferase METTL3 catalyzes m6A modification of ITGB1 mRNA, enhancing its stability through recognition by the reader protein HuR and promoting prostate cancer bone metastasis [56]. Conversely, in diabetic retinopathy, KAT1-mediated histone acetylation activates YTHDF2 expression, which recognizes m6A-modified ITGB1 mRNA and promotes its degradation, thereby reducing retinal inflammation and pathological angiogenesis, providing a solid example of cross-talk between epigenetic and epitranscriptomic regulation [12]. The therapeutic potential of targeting this layer is demonstrated by a dCasRx-based m6A editor that specifically demethylates ITGA6 mRNA, inhibiting bladder cancer cell proliferation and tumorigenesis [55].

Beyond RNA methylation, DNA methylation of integrin gene promoters provides a stable, long-term regulatory mechanism. Hypermethylation silences integrin α4 expression in breast cancer, while hypomethylation enhances integrin β7 expression in multiple myeloma, promoting cell adhesion-mediated drug resistance [49, 51]. Histone methylation, catalyzed by methyltransferases such as SMYD3, activates integrin gene transcription through H3K4me3 deposition, driving ovarian cancer peritoneal metastasis [52].

Most directly, protein arginine methylation by PRMT6 at integrin α4 Arg464 inhibits fibrotic signaling in alcohol-associated liver disease, with reduced methylation levels driving fibrosis progression [59]. These multi-level methylation events are increasingly recognized as therapeutic targets, with inhibitors against METTL3, SMYD3, and activators of PRMT6 under active investigation [52, 59, 72].

Acetylation: a dual-layer regulator of integrin function

As with methylation, acetylation regulates integrin function at two distinct levels, namely direct modification of lysine residues on integrin proteins and N4-acetylcytidine (ac4C) modification of integrin mRNAs, revealing an unexpected versatility in this PTM type [33, 61, 63]. The net effect of acetylation depends on the subcellular context: nuclear acetyltransferases and deacetylases primarily influence integrin expression through mRNA modification, while their cytoplasmic and extracellular counterparts directly modulate integrin protein conformation and interactions. Therefore, we discuss these two situations together to clarify the crosstalk between different levels of acetylation.

Protein-level acetylation directly alters integrin conformation and binding properties. Acetylation of integrin β1 at Lys794 enhances its binding to kindlin-2, disrupting endothelial cell junctional integrity and promoting abnormal tumor angiogenesis [61]. Conversely, the extracellular deacetylase SIRT2 removes acetylation from integrin β3 at Lys416, weakening cell adhesion and promoting lung cancer cell migration and metastasis. This finding challenges the conventional view of deacetylases as exclusively nuclear or cytoplasmic enzymes [62]. At the RNA level, the acetyltransferase NAT10 catalyzes ac4C modification of ITGB3 mRNA, enhancing its stability and driving osteosarcoma cell proliferation, invasion, and tumorigenesis [63]. Beyond direct integrin modification, integrin α7β1 signaling can influence global epigenetic states by reducing H3K27me3 and increasing H4 acetylation, thereby repressing intestinal absorptive cell differentiation and affecting tumor progression [73].

Abnormal acetylation is closely associated with tumor angiogenesis, cancer metastasis, and osteosarcoma progression [61–63]. The discovery of non-classical extracellular deacetylase function and ac4C-mediated RNA regulation has expanded the therapeutic landscape, with NAT10 and SIRT2 emerging as potential drug targets. Future studies investigating cross-talk between protein-level and RNA-level acetylation, as well as its intersection with other PTM types, will be essential for understanding the full scope of acetylation-mediated integrin regulation.

Nitrosylation: connecting redox signaling to integrin function

Nitrosylation, primarily S-nitrosylation mediated by nitric oxide (NO), represents a key mechanism linking cellular redox status to integrin function [65, 66]. This reversible modification targets specific cysteine residues on integrins, directly altering their conformation, activity, and stability in response to oxidative and nitrosative stress. Through this mechanism, nitrosylation serves as a critical node integrating metabolic and inflammatory signals with cell adhesion dynamics [74].

The functional consequences of integrin nitrosylation are context-dependent and often oppose other PTMs. S-nitrosylation of integrin αIIbβ3 reverses its activation state, inhibiting platelet aggregation and suggesting a protective role against thrombosis [66]. Conversely, S-nitrosylation of integrin β1 at Cys555 competitively inhibits c-Cbl-mediated ubiquitination, stabilizing the integrin and enhancing monocyte-endothelial adhesion [65]. This creates a positive feedback loop that drives vascular inflammation. In prostate cancer, iNOS-mediated S-nitrosylation of integrin α6 at Cys86 enhances its association with β1, promoting cell migration while weakening adherence to laminin-1 [64]. In diabetic nephropathy, VEGF-A knockdown and eNOS deficiency disrupt glomerular S-nitrosylation homeostasis, leading to filtration barrier breakdown and renal failure [67].

Dysregulated nitrosylation plays pivotal roles in cardiovascular disease, thrombosis, tumor metastasis, and diabetic complications [65–67, 74]. The recognition that integrins serve as both sensors and amplifiers of redox signals has important therapeutic implications. Modulating NO donors or iNOS activity may restore normal integrin function in inflammatory and metabolic diseases [7, 74]. Understanding the site-specific effects of S-nitrosylation across different disease contexts, as well as its cross-talk with ubiquitination and phosphorylation, represents an important direction for future research [72].

Beyond the classics: emerging metabolite-driven modifications of integrins

Beyond canonical enzyme-regulated PTMs, emerging evidence has uncovered non-enzymatic modifications, including carbamoylation and cysteine carboxyethylation, driven by metabolic byproducts that directly modify integrins, linking environmental factors to disease [13, 69]. These modifications arise from chemical reactions of metabolic intermediates with specific amino acid residues and are increasingly recognized as mediators of pathology in chronic kidney disease and autoimmune disorders [13, 69].

In end-stage renal disease, urea-derived cyanate carbamoylates integrin αIIbβ3 at Lys185 of the β3 subunit, altering integrin conformation and inhibiting platelet activation, providing a mechanistic link between uremia and bleeding diathesis in hemodialysis patients [13]. Free amino acid supplementation prevents this effect in vitro, suggesting a potential clinical intervention. Gut microbiota-derived 3-hydroxypropionic acid drives cysteine carboxyethylation of integrin αIIb at Cys96, generating a neoantigen presented by HLA-DRB1*04 that stimulates autoreactive CD4⁺ T cell responses and contributes to ankylosing spondylitis pathogenesis [69].

These discoveries establish a direct “metabolite-integrin-disease” axis wherein environmental metabolic perturbations generate functionally altered or immunogenic integrin variants. Future studies will likely uncover additional metabolite-driven integrin modifications in other pathological contexts, and targeting the underlying metabolic disturbances or the modifying metabolites themselves may offer novel therapeutic opportunities.

Discussion and prospects

The past decade has fundamentally reshaped our understanding of integrin biology. Once viewed primarily as static adhesion receptors whose function was dictated by expression levels and subunit composition, integrins are now recognized as dynamic signal integration platforms. Every aspect of these platforms, from folding and trafficking to activation, signaling, and turnover, is exquisitely controlled by a diverse and interconnected network of post-translational modifications [7]. As this review has systematically documented, this integrin PTM code encompasses modifications as varied as the sugar coats of glycosylation, the reversible switches of phosphorylation, the stability arbiters of ubiquitination, and the metabolite-driven alterations of carbamoylation. Yet, despite substantial progress, our understanding of this code remains fragmentary, and several critical challenges and opportunities lie ahead.

A central challenge moving forward is to move beyond cataloging individual modifications toward understanding how they function as an integrated network. The examples of PTM cross-talk scattered throughout this review, namely phosphorylation creating docking sites for ubiquitination machinery [10], glycosylation status influencing susceptibility to nitrosylation [65], and acetylation at the protein level coexisting with ac4C modification at the RNA level [61, 63], likely represent the tip of a much larger iceberg. Systematic mapping of these interdependencies will require advances in multiplexed proteomic technologies capable of simultaneously detecting multiple modification types on the same integrin molecule, as well as sophisticated computational approaches to model PTM dynamics [72]. Equally important is understanding the spatiotemporal dynamics of these modifications in living cells. The recent development of FRET-based biosensors for integrin β1 phosphorylation has already revealed that NPxY site phosphorylation is dynamically modulated during different stages of cancer cell invasion [2, 10], and similar tools for other PTMs would transformer our understanding of how the integrin PTM code is read and written in real time. A recent study on MERTK-integrin crosstalk in efferocytosis (the phagocytic clearance of apoptotic cells) further illustrates how integrin activation states are dynamically coordinated with upstream signaling receptors, suggesting that PTM dynamics may be integrated within larger signaling complexes rather than acting in isolation [75].

While this review has focused heavily on cancer, reflecting the emphasis of current literature, integrin PTMs are likely to play equally critical roles in a broad spectrum of other pathologies. Fibrotic diseases, for example, are driven by persistent integrin-mediated TGF-β activation, and emerging evidence implicates USP10-mediated deubiquitination of integrins β1 and β5 in this process [46]. The role of integrin PTMs in neurodegeneration remains largely unexplored, but given the importance of cell-matrix interactions in neuronal survival and synaptic plasticity, this represents a fertile ground for future investigation [72]. Autoimmune diseases, as illustrated by the discovery of carboxyethylated integrin αIIb neoantigens in ankylosing spondylitis [69], reveal how metabolite-driven modifications can generate immunogenic integrin variants that trigger autoreactive T cell responses. This “metabolite-integrin-immune axis” may extend to other chronic inflammatory conditions and warrants systematic exploration. Beyond direct integrin modifications, PTMs of extracellular matrix ligands represent an additional layer of indirect regulation that can profoundly alter integrin-mediated adhesion. Examples include citrullination of collagen II in rheumatoid arthritis and carbamylation of type I collagen in renal insufficiency [76]. Understanding how these extracellular modifications intersect with the integrin PTM code itself will be essential for a complete picture of adhesion regulation in disease.

The relative clinical disappointment of first-generation integrin antagonists, which broadly blocked ligand binding and suffered from efficacy and safety limitations [77], has underscored the need for more nuanced therapeutic strategies. Targeting the enzymes that write, read, or erase specific disease-associated PTMs offers precisely such nuance. Isoform-selective inhibitors of glycosyltransferases like MGAT5 [26] or methyltransferases like SMYD3 [52] are already under preclinical investigation. However, the most transformative opportunity may lie in emerging technologies that directly leverage the cell’s own PTM machinery for therapeutic benefit. PROTACs recruit E3 ubiquitin ligases to induce ubiquitination and degradation of specific target proteins, and have already advanced to clinical trials for several oncology indications [78]. Given that multiple E3 ligases, including CBL, CUL5, and NEDD4L, naturally regulate integrin stability [42, 43, 48], harnessing these same ligases with integrin-directed PROTACs represents a logical therapeutic extension. The recent development of lysosome-targeting chimeras (LYTACs) further enables degradation of membrane proteins, making integrins particularly attractive LYTAC targets [79]. Conversely, in pathological conditions where integrin loss or instability drives disease, such as the carbamoylation-induced integrin degradation in uremic bleeding [13], strategies to stabilize integrins may be therapeutically beneficial. DUBTACs represent an emerging modality that recruits deubiquitinases to remove ubiquitin chains and stabilize target proteins [80, 81]. This approach directly parallels the endogenous role of deubiquitinases like USP10 and USP12/46 in protecting integrins from degradation [46, 47]. The conceptual symmetry between PROTACs (degradation) and DUBTACs (stabilization) illustrates how understanding endogenous PTM regulatory networks can inspire bidirectional therapeutic strategies. Parallel advances in PTM editing tools, such as the dCasRx-m6A editor used to demethylate ITGA6 mRNA in bladder cancer [55], open up additional possibilities for precision medicine. The sialylated Lewis antigen-mediated interactions between tumor exosomes and endothelial selectins further highlight how glycosylation-based recognition could be targeted therapeutically [82].

The study of integrin post-translational modifications has matured from a collection of isolated observations into a coherent and rapidly advancing field. We now realize that integrins not only function outside of cells, but they themselves are also responsible for complex intracellular regulation through a series of classical and novel modifications. Understanding how modifications cooperate, compete, and cascade to dictate integrin function in health and disease is the essence of deciphering this code. This represents one of the great challenges and opportunities in cell adhesion biology. As technologies for PTM detection, imaging, and manipulation continue to advance, we can look forward to a future where the integrin PTM code is not only read but also rewritten for therapeutic benefit.

Author contributions

Xiao Wu drafted the manuscript and prepared the figures and tables. Xiaofan Wei conceived the idea, designed the study, and critically revised the manuscript. Hongquan Zhang critically revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by grants from National Natural Science Foundation of China (82473050) and the Beijing Natural Science Foundation (7242088).

Data availability

Not applicable.

Declarations

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Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.