The landscape of protein post-translational modifications in the pathogenesis of acute respiratory distress syndrome

Introduction

Acute respiratory distress syndrome (ARDS) represents a devastating clinical syndrome marked by diffuse alveolar damage, refractory hypoxemia, and non-cardiogenic pulmonary edema (1,2). The etiology is complex, encompassing direct and indirect pulmonary insults that include severe infection, trauma, and shock (3,4). Despite decades of research and advances in supportive care, the mortality rate for ARDS remains alarmingly high, ranging from 30% to 40% (5). The pathological hallmark centers on alveolar-capillary barrier disruption coupled with an uncontrolled inflammatory response, commonly termed the “cytokine storm” (6). Yet pharmacological progress remains limited overall, as only a few interventions show benefit in highly selected settings, while most fail to demonstrate consistent efficacy in adequately powered phase III trials (7). This persistent gap suggests that we still do not have a sufficiently clear picture of what happens during the very first hours of lung injury at the molecular level.

The onset of ARDS is often explosive, occurring rapidly after insults such as sepsis, trauma, or pneumonia. While changes at the gene transcription level are certainly important for longer-term adaptation of cells, they are generally too slow to account for the explosive events that occur in the first minutes to hours (8). In contrast, post-translational modifications (PTMs) allow cells to regulate existing proteins rapidly, reversibly, and with high precision, without having to synthesize new ones (9). PTMs involve the covalent attachment of chemical groups including phosphate, ubiquitin, acetyl, or methyl groups to specific amino acid residues (10,11), acting as rapid “molecular switches”. These modifications can instantaneously alter protein stability, enzymatic activity, subcellular localization, and protein-protein interactions, thereby dictating the fate of alveolar epithelial and endothelial cells under stress (12). The full range of PTMs is actually quite broad, going well beyond the classical ones to include lipidation, various forms of glycosylation, methylation, biotinylation, sulfation, and several less well-characterized additions.

Most earlier work on PTMs in ARDS has concentrated on phosphorylation events, particularly those feeding into the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways that drive inflammation (13,14). The injured lung is characterized by a hypoxic and highly metabolic microenvironment, leading to the accumulation of various metabolites including lactate (15), succinate (16), and acetyl-CoA (17). There is now substantial evidence that some of these metabolites are not merely fuel molecules but can also donate groups for protein modifications. The most prominent examples include lactylation, succinylation, and acetylation. These modifications directly connect metabolic rewiring to immune cell behavior, a relationship now commonly called “immunometabolism” (18). For instance, recent discoveries regarding histone lactylation (19) and citrullination (20) have highlighted novel epigenetic mechanisms that perpetuate inflammation and tissue damage, offering fresh perspectives on the pathogenesis of ARDS.

In the present review, we attempt to summarize what is currently understood about the major classes of PTMs in ARDS pathogenesis. We first discuss the classical modifications, specifically phosphorylation and ubiquitination, and how they regulate inflammatory signaling and barrier function. We then examine several more recently appreciated PTMs, notably citrullination and lactylation, and their links to neutrophil extracellular trap (NET) formation, macrophage functional changes, and other key processes. Finally, we discuss the therapeutic potential of targeting specific PTM-modifying enzymes, underscoring how multi-omics integration with targeted interventions may help surmount existing translational barriers against this life-threatening syndrome. The spatiotemporal relationships, regulatory hierarchy, and dominant roles of PTMs across ARDS phases are summarized in Figure 1. Figure 2 maps each PTM type to the six core pathological processes of ARDS, serving as a navigational guide for “Phosphorylation: the master switch in ARDS signaling”, “Ubiquitination and deubiquitination: regulating protein stability”, “Acetylation: epigenetic and metabolic regulation”, “Emerging PTMs and crosstalk in ARDS”, “Metabolite-driven regulation of the PTM landscape in ARDS”, and “Crosstalk between PTMs” sections.

Figure 1 The spatiotemporal landscape of post-translational modifications in ARDS pathogenesis. The horizontal axis represents ARDS progression through three phases: initiation (<6 h), exudative (6–72 h), and resolution/fibrosis (>72 h). The vertical axis organizes PTMs into three regulatory layers by timescale: rapid signaling switches (phosphorylation, seconds–minutes), protein fate control (ubiquitination/deubiquitination, minutes–hours), and metabolic-epigenetic reprogramming (acetylation, citrullination, lactylation, succinylation, hours–days). The bottom panel illustrates how metabolic intermediates drive PTM enzyme activity (left) and the crosstalk network among PTM types (right). Colored dots indicate primary cell types involved (blue: endothelial; green: epithelial type II; orange: macrophage; purple: neutrophil). ARDS, acute respiratory distress syndrome; PTM, post-translational modification.

Figure 2 Mapping of post-translational modifications to core pathological events in ARDS. Rows represent the 10 major PTM types discussed in this review. Columns represent six core pathological processes in ARDS. Filled circles indicate a major regulatory role supported by substantial evidence; open circles indicate a secondary or indirect role; Blank indicates that their participation was not reported. Representative target proteins are annotated beneath each circle. Top color bars indicate the ARDS phase in which each pathological event predominates. ARDS, acute respiratory distress syndrome; PTM, post-translational modification.

Phosphorylation: the master switch in ARDS signaling

Protein phosphorylation, controlled by the opposing actions of kinases and phosphatases, remains the most frequently studied PTM in cell biology (21). In the pathophysiology of ARDS, these events appear to serve as one of the key fast-acting control points. They convert extracellular danger signals, such as pathogen-associated molecular patterns (PAMPs) (22,23) and hypoxia (24), into intracellular responses that unfold within seconds to minutes. Transcriptional changes, by contrast, usually take hours and therefore cannot account for the very earliest explosive phase of lung injury (25). Accordingly, phosphorylation-dependent signaling governs three key processes in ARDS: inflammatory amplification, endothelial barrier failure, and impaired alveolar fluid clearance (AFC). Whether these processes are truly independent or more intertwined than current models suggest is still not entirely clear, but their regulation by phosphorylation is consistently observed across preclinical acute lung injury studies.

MAPK, NF-κB, and JAK-STAT pathways: drivers of the cytokine storm

The “cytokine storm”, characterized by widespread and dysregulated release of pro-inflammatory mediators, serves as the primary driver of multi-organ failure in ARDS (26). Much of this dysregulated response depends on phosphorylation events downstream of pattern recognition receptors, with Toll-like receptor 4 (TLR4) serving as one of the most important entry points.

The MAPK pathway is frequently activated following TLR4 ligation by lipopolysaccharide (LPS) or damage-associated molecular patterns (DAMPs). This leads to MyD88-dependent recruitment and subsequent engagement of the three main branches, namely ERK1/2, JNK, and p38 (27-30). Activated ERK1/2 can translocate to the nucleus and phosphorylate transcriptional regulators, thereby accelerating induction of cytokines and contributing to epithelial and endothelial injury (31,32).

Coordinated with MAPKs, the NF-κB pathway acts as a central inflammatory hub. IKKβ phosphorylates IκBα at Ser32/36, marking it for degradation and releasing the p65/p50 dimer for nuclear translocation (33,34). p65 itself undergoes phosphorylation at Ser536 in its transactivation domain, enhancing recruitment of transcriptional co-activators including CREB-binding protein (CBP)/p300 and amplifying chemokine transcription, particularly IL-8 (35-37). However, this picture is not uniform: recent work has shown that Ser536 phosphorylation can be highly cell-type and stimulus dependent in lung injury settings. In some contexts, it may even initiate negative feedback, limit certain anti-inflammatory programs, or promote transcriptional fatigue (38-40). Levels of p65 phosphorylation have been repeatedly linked to increased vascular permeability, edema severity, and inflammatory intensity, and may also feed into metabolic shifts (41-43).

The JAK-STAT pathway often serves as a secondary amplification loop. Secreted IL-6 triggers JAK-mediated phosphorylation of STAT3 at Tyr705. Persistent p-STAT3 signaling has been linked to the transition from acute inflammation to fibrosis, and JAK inhibitors have shown efficacy in dampening this amplification loop in coronavirus disease 2019 (COVID-19) ARDS (44-46). Whether similar benefit extends reliably to non-viral or heterogeneous ARDS subsets remains less certain.

Myosin light chain (MLC) and vascular endothelial (VE)-cadherin: mechanisms of endothelial barrier dysfunction

Pulmonary endothelial barrier disruption, a hallmark of ARDS causing protein-rich edema, is an active mechanical process driven by two key phosphorylation-dependent mechanisms: actomyosin hyper-contractility and adherens junction disassembly.

Endothelial cells generate centripetal contractile forces capable of separating neighboring cells. A critical determinant of this force is phosphorylation of MLC, regulated by myosin light-chain kinase (MLCK) and reversed by myosin light-chain phosphatase (MLCP) (47). Phosphorylation of MLC at Thr18 and Ser19 promotes contraction of pulmonary microvascular endothelial cells, widening paracellular gaps and compromising junctional integrity. The causal role of this pathway is well-established; genetic ablation of MLCK or the use of specific inhibitors for example, ML-7, significantly reduces lung edema and mortality in murine models of ARDS (48). Furthermore, this contraction is sustained by the RhoA/ROCK pathway, which phosphorylates the myosin phosphatase targeting subunit (MYPT1), inhibiting the phosphatase responsible for dephosphorylating MLC (49,50). This coordinated activation of kinase signaling and suppression of phosphatase activity locks endothelial cells in a hyper-contractile state. Recent studies in sepsis-induced ARDS models further confirm the critical role of RhoA/ROCK-mediated MYPT1 phosphorylation in exacerbating endothelial hyperpermeability and pulmonary edema (50,51).

The adhesive integrity of the barrier is compromised by the phosphorylation of VE-cadherin, the key component of adherens junctions (34). Under homeostatic conditions, VE-cadherin is anchored to the cytoskeleton via p120-catenin and β-catenin. However, during ARDS, Src family kinases are rapidly activated and phosphorylate VE-cadherin at specific tyrosine residues, most notably Tyr658 and Tyr731 (52). These phosphorylation events induce the internalization and lysosomal degradation of VE-cadherin, thereby exacerbating pulmonary vascular leakage. Earlier studies using knock-in mice with non-phosphorylatable VE-cadherin mutants (such as Y658F) suggested that blocking phosphorylation at these tyrosine sites could help maintain barrier integrity despite strong inflammatory challenges (34,53). However, more recent in vivo work has painted a more complicated picture: the Y658F mutation often fails to protect against vascular leak triggered by various inflammatory mediators, whereas phosphorylation at serine 665 (and to some extent Y685) appears more critical in driving permeability changes in inflamed vessels (53).

Overall, the combined effect of MLC-driven contractile pull and Src-dependent disassembly of adherens junctions remains one of the main drivers of vascular hyperpermeability in ARDS. In addition, spleen tyrosine kinase (Syk) has been identified as another kinase that can phosphorylate VE-cadherin and contributes to endothelial barrier breakdown, particularly in sepsis-associated acute lung injury models (52). That said, the relative importance of Syk in non-septic or more heterogeneous ARDS subtypes still needs further clarification.

Na, K-ATPase phosphorylation: impairing AFC

The resolution of pulmonary edema relies on AFC, depends heavily on Na, K-ATPase located in alveolar type II cells. In ARDS, one major reason for failed fluid resolution is altered trafficking and removal of this pump from the cell surface, often driven by phosphorylation.

The surface density of Na, K-ATPase is tightly controlled by protein kinase C (PKC), specifically the protein kinase C zeta (PKCζ) isoform. In the setting of acute lung injury induced by hypoxia (54), hypercapnia (55), or viral infection (56). PKCζ translocates to the plasma membrane and phosphorylates the Na, K-ATPase α-subunit at Ser18. This specific modification creates a binding motif for the adaptor protein AP-2, leading to clathrin-dependent endocytosis and subsequent intracellular degradation of the pump (57). The net result is loss of surface pump density and collapse of the sodium gradient needed for fluid reabsorption. In contrast, a modification that stabilizes membrane localization and enhances enzymatic turnover (58). This opposing phosphorylation pattern, where Ser18 promotes internalization and Ser943 supports membrane retention, provides a mechanistic basis for β-adrenergic agonists as AFC-enhancing therapies in experimental models (59).

However, large randomized controlled trials (RCTs) have shown that continuous intravenous infusion of β-agonists does not significantly improve 28-day survival in ARDS patients and may even increase adverse events (60). This translational discrepancy likely reflects multiple converging factors rather than phosphorylation control alone, including rapid desensitization of β2-adrenergic receptors, attenuation of cAMP signaling, the high biological heterogeneity of ARDS patients, and strict limitations on the therapeutic time window (3,61,62). These repeated failures remind us that phosphorylation mechanisms elucidated in clean animal models may capture only part of the story in real-world, heterogeneous ARDS. Together, this underscores the importance of moving toward subphenotype-stratified approaches and very careful timing when testing any intervention aimed at restoring AFC.

Ubiquitination and deubiquitination: regulating protein stability

While phosphorylation typically functions as a quick on-off switch for enzyme activity, ubiquitination more straightforwardly controls protein stability, localization, and fate. In the pathogenesis of ARDS, the ubiquitin-proteasome system (UPS) does more than just maintain protein quality, it also acts as a fine-tuner of inflammatory strength (63). Whether lung injury resolves or moves toward fibrosis largely depends on the balance between E3 ubiquitin ligases and deubiquitinases (DUBs).

The UPS: an inflammatory driver

The cytokine storm is closely tied to UPS-dependent proteolysis through canonical NF-κB activation. NF-κB is retained in the cytoplasm by IκBα; upon TLR4 stimulation, the SCF-β-TrCP E3 ligase recognizes phosphorylated IκBα and catalyzes K48-linked polyubiquitination (64). K48 chains mark the protein for proteasomal degradation signal, directing IκBα to the 26S proteasome (65). This degradation event swiftly liberates the NF-κB p65/p50 heterodimer to enter the nucleus (66). In ARDS, this mechanism can create a double problem: while proteasomal IκBα turnover promotes inflammatory gene expression, proteasome-dependent Nrf2 turnover can weaken antioxidant defenses (67). The combination of stronger NF-κB activity and poorer cytoprotection likely worsens tissue damage (68,69).

E3 ligases: specificity and “double-negative” control

Broad pharmacological inhibition of the proteasome, including with bortezomib, is limited by significant systemic and pulmonary toxicity, which complicates its application in acute lung injury treatment (70). Consequently, research has pivoted toward E3 ubiquitin ligases, which confer high substrate specificity and represent promising druggable targets.

A standout example in ARDS biology is F-box protein 3 (FBXO3), an E3-ligase component that fuels inflammation through an “inhibitor-of-an-inhibitor” mechanism (71). Its target is F-box and leucine rich repeat protein 2 (FBXL2), a protective protein that normally degrades TRAFs to keep cytokine signaling in check. In the injured lung, FBXO3 levels rise and trigger the ubiquitination and degradation of FBXL2 (72). Once FBXL2 is gone, TRAF proteins accumulate and further amplify the inflammatory response. Accordingly, small-molecule inhibitors of FBXO3 such as BC-1215 have produced very encouraging results in models (71).

E3 ligases can also organize signaling without causing degradation. Pellino-1, activated downstream of the IRAK complex (73), catalyzes K63-linked polyubiquitination of RIPK1. Unlike K48 chains, K63 chains act as scaffolds recruiting the TAK1-TAB complex (74), enabling robust MAPK and NF-κB activation. In murine models of ARDS (75), Pellino-1 deletion attenuates septic lung injury, reducing neutrophil infiltration and pro-inflammatory cytokine production. This distinction, in which K48 chains promote degradation whereas K63 chains organize signal transduction, highlights the versatility of E3 ligases in inflammatory control.

DUBs: ubiquitin “editing”

Just as kinases are counterbalanced by phosphatases, E3 ligases are restrained by DUBs (76). In ARDS, persistent hyperinflammation may reflect loss or insufficiency of these negative regulators, rather than pure overdrive of activating pathways (77).

A20 (TNFAIP3) is a canonical anti-inflammatory DUB that terminates signaling via “ubiquitin editing” (78). A20 possesses a unique dual functionality (79): its N-terminal OTU domain removes K63-linked ubiquitin chains from TRAF6, whereas its C-terminal zinc-finger domain facilitates degradation-associated K48-linked ubiquitination of the same substrate (80,81). This sequential removal-and-retagging mechanism suppresses TLR4 signaling. Evidence suggests that A20 expression can be compromised in severe ARDS through epigenetic silencing (82) or viral proteolysis (83), thereby permitting sustained NF-κB activation.

CYLD complements A20 by removing K63-linked chains from NEMO, limiting kinase recruitment (77). OTULIN, a Met1-specific DUB, cleaves linear ubiquitin chains generated by LUBAC (84), keeping TNF receptor signaling under control (85). Loss-of-function mutations in OTULIN lead to severe systemic autoinflammatory syndromes characterized by dysregulated TNF/NF-κB signaling and excessive inflammatory cytokine production (86), underscoring the indispensability of removing linear ubiquitin chains to maintain immune homeostasis.

Mitophagy and ubiquitination: the PINK1-Parkin axis

Beyond cytosolic signaling, ubiquitination is central to organelle quality control, particularly mitophagy (87). In ARDS, oxidative stress promotes accumulation of damaged, depolarized mitochondria (12). Without clearance, mitochondria-derived ROS and mtDNA can enter the cytosol and activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome (88,89).

The PINK1-Parkin pathway acts as the primary guardian of mitochondrial integrity (90). Normally, PINK1 is imported into mitochondria and degraded. Upon membrane potential collapse, an ARDS hallmark, PINK1 stabilizes on the OMM, recruiting and activating Parkin, a cytosolic E3 ligase (91,92). Activated Parkin ubiquitinates OMM proteins like VDAC1 and Mfn2 (90), generating signals recognized by p62/SQSTM1 and OPTN (93). These receptors physically tether the ubiquitinated mitochondria to the LC3-positive autophagosome, facilitating their delivery to lysosomes for degradation (94).

In severe ARDS, mitophagy can be overwhelmed or inhibited, allowing damaged mitochondria to accumulate and promoting NLRP3 activation driven by oxidized mtDNA, alongside IL-1β and IL-18 maturation (95). A compelling illustration of targeting this axis is the potential repurposing of metformin (96), which inhibits NLRP3 assembly mainly via AMPK activation and mTOR suppression, reducing mtROS and mtDNA release. This disrupts mitochondrial dysfunction-pyroptosis links, attenuating inflammation in ARDS models (96-98). Yet, while effective in animals, clinical evidence is limited, requiring large RCTs for validation in heterogeneous ARDS patients.

Acetylation: epigenetic and metabolic regulation

While phosphorylation usually handles rapid, short-lived signal changes, protein acetylation, which involves the addition of an acetyl group from acetyl-CoA onto lysine side chains, more often leads to longer-lasting shifts in cell behavior (99). In the complex pathogenesis of ARDS, acetylation seems to work at two related levels: epigenetically remodeling chromatin to “unlock” the inflammatory genome (12,100), and post-translationally modifying non-histone proteins (25) to dictate their subcellular trafficking and function.

Histone acetylation: unlocking the inflammatory genome

Massive early transcription of cytokines (101), most prominently TNF, IL-6, and CXCL8, requires not only transcription-factor activation but also physical access to DNA (102). This accessibility depends on the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) (103).

Under homeostatic conditions, DNA is tightly wrapped around histone octamers within compact chromatin domains, thereby limiting transcriptional accessibility (104,105). Upon inflammatory stimulation mediated by LPS or TLR4 signaling (106), p300/CBP are recruited to regulatory regions and acetylate conserved lysines on H3 and H4 tails (107). This modification neutralizes the positive charge of the lysine ε-amino group, weakening the electrostatic attraction between the histones and the negatively charged DNA backbone. Consequently, the chromatin structure relaxes into an “open” euchromatin state (108). This permissive structure facilitates recruitment of RNA polymerase II and transcription factors including NF-κB, enabling rapid transcriptional initiation (109). In patients with ARDS, this balance is frequently disrupted: an aberrant increase in HAT activity, often coupled with oxidative stress-induced reduction of HDAC2, leads to global histone hyperacetylation (110-112). Such epigenetic reprogramming may prime airway and alveolar cells for exaggerated responses and can delay inflammatory resolution even after pathogen clearance.

Non-histone acetylation: high mobility group box 1 (HMGB1) and NF-κB

Beyond the nucleus, acetylation serves as a critical molecular switch for HMGB1, a nuclear protein that functions as a sentinel for genomic stability (113). In sterile injury or sepsis, HMGB1 shifts to become a powerful extracellular danger signal, and this change is heavily influenced by its acetylation level.

Under normal physiological conditions, HMGB1 is kept in the nucleus via two specific nuclear localization signals (NLS) (114). During lung injury, inflammatory cues promote nuclear activity of acetyltransferases including PCAF and CBP (115), leading to hyperacetylation of lysines within HMGB1 NLS motifs. This acetylation reduces NLS function and impairs nuclear re-import, causing cytoplasmic accumulation and subsequent packaging into secretory lysosomes for extracellular release (116). Once extracellular, acetylated HMGB1 functions as a strong DAMP, binding to RAGE and TLR4 trigger a later, more sustained round of cytokine production (117,118). Unlike early mediators such as TNF-α, HMGB1 acts as a relatively late inflammatory mediator with sustained elevation after injury (113), which has made it a suspect in delayed organ dysfunction (115). Accordingly, interrupting acetylation-dependent HMGB1 translocation and release may offer a time-defined therapeutic opportunity in established ARDS (119), although whether this strategy holds up in heterogeneous patients still needs more testing.

Sirtuins (SIRTs): the metabolic brake on inflammation

Opposing HAT-driven acetylation, SIRTs are nicotinamide adenine dinucleotide⁺ (NAD⁺)-dependent deacetylases that sense cellular metabolic state (120,121). In ARDS, intracellular NAD⁺ depletion can compromise sirtuin activity and thereby exacerbate inflammation (122).

SIRT1 helps limit inflammatory gene expression by removing the acetyl group from NF-κB p65 at Lys310, a modification required for full NF-κB transactivation capacity (123,124). Deacetylation here selectively reduces pro-inflammatory gene expression without necessarily disrupting DNA binding. Notably, SIRT1 are clearly context-dependent: while predominantly anti-inflammatory in ARDS models, its net impact can vary with disease stage and metabolic state, underscoring regulatory complexity (125,126).

In parallel, mitochondrial SIRT3 preserves redox balance by deacetylating and activating superoxide dismutase 2, a key mitochondrial antioxidant enzyme. In ARDS, reduced SIRT3 activity promotes superoxide dismutase 2 hyperacetylation and functional impairment, increasing mtROS and potentiating NLRP3 inflammasome activation. Therapeutic approaches that restore NAD⁺ availability or activate sirtuins may therefore provide dual leverage, specifically by limiting nuclear inflammatory output via SIRT1 while reinforcing mitochondrial antioxidant defenses via SIRT3.

Emerging PTMs and crosstalk in ARDS

Beyond canonical modifications, emerging PTMs, particularly citrullination, lactylation, and succinylation, have been linked to metabolic stress, immune dysregulation, and tissue damage in ARDS. Most data come from preclinical models and are highly context-sensitive, suggesting that citrullination promotes NET formation, lactylation can reshape acute injury programs including ferroptosis-related pathways, and succinylation perturbs mitochondrial metabolism. These intersections highlight PTM crosstalk as a potential entry point for precision, cell- and phase-informed interventions.

Citrullination: a trigger of NETosis

NETs are web-like structures of DNA and enzymes that cause significant endothelial injury in ARDS (102). The formation of NETs is strictly dependent on histone citrullination, a reaction catalyzed by peptidylarginine deiminase 4 (PAD4) (127).

Mechanistically, PAD4 converts positively charged arginine residues on histone tails (H3 and H4) into neutral citrulline (128), disrupting the interactions between histones and DNA and driving chromatin decondensation. This step enables mixing of DNA with antimicrobial enzymes including myeloperoxidase and neutrophil elastase before extracellular release (129,130). In clinical ARDS, higher citrullinated H3 (Cit-H3) levels often track with worse disease severity (131). NETs and NET-associated components have been shown to injure alveolar epithelial cells and promote endothelial cell death, thereby increasing vascular permeability and pulmonary edema. PAD4 inhibition [Cl-amidine (20)] or genetic ablation of the Padi4 gene (132), supporting citrullination as a therapeutic target. That said, human trials remain very limited, and off-target effects or timing issues could complicate translation.

Lactylation: coupling hypoxia, metabolism, and immunity

Severe ARDS features profound hypoxia and a strong shift toward glycolysis, causing lactate buildup. Lactate can serve as a substrate for lysine lactylation (Kla), with histone marks such as H3K18la and H3K14la providing a direct route from metabolism to transcriptional control (133).

Initial studies linked lactylation to macrophage reprogramming toward reparative states via promoter enrichment of H3K18la at pro-resolution genes (134-137). More recent work, however, has associated lactylation with detrimental programs during the acute phase of sepsis-associated lung injury (138). Histone lactylation drives ferroptosis in pulmonary microvascular endothelial cells, thereby exacerbating vascular permeability and lung injury progression (139,140). Mechanistically, H3K18la and H3K14la accumulate at promoters of ferroptosis-related genes including those encoding transferrin receptor and solute carrier family 40 member 1, enhancing iron uptake, lipid peroxidation, and endothelial damage (141). Concurrently, lactylation elevates METTL3 expression via promoter enrichment of H3K18la, increasing m6A modification and stabilizing ACSL4 mRNA to amplify polyunsaturated fatty acid esterification and ferroptosis execution (139). In addition, H3K18la-driven Egr1 upregulation has been linked to heparanase activation and endothelial glycocalyx degradation, worsening pulmonary edema (142). In alveolar epithelial cells, H3K18la promotes caspase-8 expression, sensitizing cells to TNF-α-induced apoptosis (143). Non-histone lactylation has also been implicated, with LPCAT2 K375 lactylation reported to repress SLC7A11 through STAT1 modulation and thereby promote epithelial ferroptosis (19).

Although certain contexts indicate lactate attenuates PANoptosis in macrophages through ZBP-1 lactylation (144), such protective effects appear limited and insufficient to counteract predominant pro-injury actions in sepsis models. Human data are still very sparse, and conflicting results appear in non-ARDS contexts. Lactylation thus integrates hypoxia, metabolism, and immunity but predominantly aggravates acute lung injury in preclinical sepsis-ARDS models. Any attempt to modulate it would need very careful stratification by disease phase and cell type to avoid blocking useful reparative programs.

Succinylation: a metabolic blockade

Mitochondrial dysfunction represents a central hallmark of ARDS pathophysiology (145). Disruption of the tricarboxylic acid (TCA) cycle causes succinyl-CoA to build up, allowing non-enzymatic lysine succinylation, a bulky, negatively charged modification that alters protein structure and function (146,147).

In lung injury models, increased succinylation has been noted on key mitochondrial enzymes such as isocitrate dehydrogenase 2 and pyruvate dehydrogenase, often linked to reduced TCA flux and impaired respiration (148-150). Such metabolic impairment may compromise fatty acid oxidation (FAO) in alveolar type II cells (151). Because FAO supports acetyl-CoA supply for dipalmitoylphosphatidylcholine (DPPC) synthesis, succinylation-linked metabolic constraint could contribute to surfactant insufficiency, alveolar instability, and refractory hypoxemia in severe ARDS (152,153).

However, direct evidence tying succinylation to FAO blockade and subsequent surfactant impairment in ARDS is still quite limited and mostly indirect; most associations derive from broader metabolic contexts or sepsis-associated models, with solid lung-specific confirmation still lacking. Rigorous validation in relevant lung compartments and time windows is therefore required before succinylation can be positioned as a therapeutic driver of refractory hypoxemia.

Other PTMs with potential relevance to lung injury

Beyond the established PTMs, several additional modifications are gaining attention as possible regulators in ARDS pathogenesis, though their evidence base remains weaker than for the main ones discussed above. SUMOylation plays a pivotal role in the lung’s response to hypoxia and stress. It stabilizes key transcription factors and modulates NF-κB activation, thereby orchestrating the inflammatory response under low-oxygen conditions characteristic of ARDS (154,155).

Protein glycosylation, particularly O-GlcNAcylation, has emerged as a critical nutrient sensor that links metabolic status to immune regulation. Recent findings indicate that enhanced O-GlcNAcylation of NF-κB and mitochondrial proteins during acute stress can exacerbate inflammatory cytokine production and oxidative damage in alveolar epithelial cells (156,157).

Lipidation, specifically S-palmitoylation, governs the membrane association and spatial organization of signaling proteins. It has been reported that the palmitoylation of endothelial junction proteins including VE-cadherin and small GTPases is essential for maintaining the endothelial barrier (158). Dysregulation of palmitoyltransferases (DHHCs) may contribute to the vascular leakage observed in ARDS (159,160).

Additionally, S-nitrosylation, a redox-dependent modification driven by nitric oxide (NO), plays a dual role in lung injury. While it can modulate surfactant protein function and inhibit specific apoptotic pathways, excessive S-nitrosylation under conditions of nitrosative stress has been associated with mitochondrial impairment and prolonged inflammation (161,162).

Metabolite-driven regulation of the PTM landscape in ARDS

A fundamental yet underappreciated regulatory layer shapes the PTM landscape in ARDS: metabolic intermediates serving as obligate co-substrates, acyl donors, or competitive inhibitors for PTM-catalyzing enzymes. The Warburg-like glycolytic shift, hypoxia-driven TCA cycle disruption, and compartment-specific accumulation of intermediates actively reshape the PTM landscape by modulating enzyme kinetics and substrate availability. Metabolic reprogramming in ARDS should therefore be understood as an upstream regulatory input into the PTM events described in “Phosphorylation: the master switch in ARDS signaling”, “Ubiquitination and deubiquitination: regulating protein stability”, “Acetylation: epigenetic and metabolic regulation”, and “Emerging PTMs and crosstalk in ARDS” sections, rather than a parallel pathological process.

The acetyl-CoA/HAT axis is perhaps the most direct illustration of this principle. The nuclear acetyl-CoA pool, which ultimately feeds CBP/p300, is sustained largely by Adenosine triphosphate-citrate lyase (ACLY), which cleaves mitochondria-exported citrate into cytoplasmic acetyl-CoA (163,164). Upon TLR4 ligation by PAMPs and DAMPs in ARDS, alveolar macrophages undergo glycolytic reprogramming with cytoplasmic citrate accumulation, driving ACLY-mediated acetyl-CoA generation (165,166). This metabolically supplied acetyl-CoA directly increases H3/H4 acetylation at NF-κB target gene promoters (18), amplifying the chromatin accessibility changes described in “Histone acetylation: unlocking the inflammatory genome” section, additively, not redundantly, with direct p65 K310 acetylation by CBP/p300. Pharmacological ACLY inhibition suppresses H3K27 acetylation at inflammatory promoters and attenuates macrophage cytokine production in endotoxemia models (165), providing proof-of-concept that metabolic acetyl-CoA flux is a tractable upstream node, even if ARDS-specific validation remains limited.

The sirtuin axis tells a complementary story from the opposite direction. SIRT1 and SIRT3 consume NAD⁺ stoichiometrically with each deacylation reaction, rendering their catalytic activity directly sensitive to intracellular NAD⁺ availability (167). Hypoxia-driven anaerobic glycolysis elevates the NADH/NAD⁺ ratio, reducing NAD⁺ availability for sirtuin-mediated diacylation (168). Concurrently, poly(ADP-ribose) polymerase 1 (PARP-1) hyperactivation in response to oxidative DNA strand breaks consumes NAD⁺ in large quantities (169); NET-derived extracellular DNA may provide an additional PARP-1-activating stimulus in the ARDS context (170,171), though the quantitative contribution of this mechanism to intracellular NAD⁺ depletion in ARDS-specific compartments warrants direct investigation.

Succinate and fumarate accumulation adds a third layer of disruption through competitive inhibition of the α-ketoglutarate (α-KG)-dependent dioxygenase family. Succinate and fumarate, accumulating in activated macrophages via well-characterized TCA remodeling (172,173), are structural analogues of α-KG and competitively inhibit hypoxia-inducible factor 1-alpha (HIF-1α) prolyl hydroxylases (PHDs), stabilizing HIF-1α through a mechanism that compounds canonical hypoxic PHD suppression (174). Importantly, this metabolite-driven HIF-1α stabilization is independent of oxygen tension and therefore persists even when oxygenation is partially restored, extending HIF-1α activity beyond the strictly hypoxic phase of ARDS. The resulting HIF-1α transcriptional program further reinforces glycolytic reprogramming and pro-inflammatory gene expression (175,176), connecting TCA disruption (“Succinylation: a metabolic blockade” section) back to the acetyl-CoA and NAD⁺ axes described above and establishing a feedforward relationship in which succinate-driven HIF-1α activation amplifies the glycolytic reprogramming that sustains both upstream metabolic axes.

These three axes indicate that a limited number of metabolic intermediates propagate broadly across the PTM landscape. Acetyl-CoA availability amplifies inflammatory PTM writing by supplying HAT co-substrate; NAD⁺ depletion disables sirtuin erasers that would otherwise reverse these modifications; and succinate accumulation perpetuates inflammatory signaling by stabilizing HIF-1α through PHD inhibition. Additional metabolite-dependent relationships, including lactyl-CoA flux governing lactylation and UDP-GlcNAc availability linking nutrient status to O-GlcNAcylation, reinforce this principle. One-carbon metabolism and S-adenosylmethionine-dependent methyltransferase regulation represent an additional axis not addressed here, warranting future investigation in ARDS. Metabolic interventions targeting these upstream nodes, such as ACLY inhibition, NAD⁺ repletion, or limiting pathological succinate accumulation, may exert PTM-level effects of greater mechanistic breadth than direct enzyme targeting. Whether this breadth translates to clinical benefit or interferes with resolution-promoting PTM events remains a question requiring disease-stage-resolved, compartment-specific investigation.

Crosstalk between PTMs

In the pathogenesis of ARDS, proteins are rarely regulated by a single type of PTM. Instead, different modifications often coexist and interact on the same protein, a phenomenon known as PTM crosstalk. Such interactions enable graded, context-dependent control of protein activity, localization, and turnover, rather than binary “on/off” regulation (177).

The phosphorylation-ubiquitination axis at IκBα exemplifies obligatorily sequential PTM crosstalk (178). IKKβ-mediated phosphorylation of IκBα at Ser32/Ser36 creates a phosphodegron that is the non-redundant prerequisite for recognition by the SCF-βTrCP E3 ubiquitin ligase complex and subsequent K48-linked polyubiquitination (179); without this priming phosphorylation, NF-κB remains sequestered. In the ARDS context, where TLR4 ligation by PAMPs and DAMPs drives rapid IKKβ activation, this sequential dependence means that IKKβ inhibition simultaneously abrogates both modifications, whereas proteasome inhibition allows accumulation of phosphorylated IκBα while preventing its degradation (33), producing mechanistically distinct downstream consequences relevant to the targeting strategies discussed in “Therapeutic potential: targeting PTMs for ARDS treatment” section.

In contrast, PTMs can also engage in competitive crosstalk. O-GlcNAcylation and phosphorylation frequently compete for occupancy at the same serine or threonine residues, with the prevailing modification determined by the relative activities of OGT, OGA, and site-specific kinases under the metabolic conditions of the cell (180,181). Under physiological conditions, Akt-mediated phosphorylation of eNOS at Ser1177 activates the enzyme, sustaining NO bioavailability, vasodilatory tone, and endothelial barrier integrity (182). Under conditions of metabolic stress, increased glucose flux through the hexosamine biosynthetic pathway elevates intracellular UDP-GlcNAc concentrations and enhances OGT activity (183). Increased O-GlcNAcylation of eNOS attenuates Akt-dependent phosphorylation at Ser1177, suppressing NO production and promoting endothelial dysfunction, as demonstrated in hyperglycemia models and is reversible upon OGA-mediated removal of the O-GlcNAc modification (184,185). Whether this attenuation reflects direct competition at Ser1177 or steric interference at a distinct site remains to be established, but the inverse relationship between eNOS O-GlcNAcylation and Ser1177 phosphorylation is well documented (186,187); whether this mechanism operates comparably in ARDS-specific pulmonary compartments warrants direct investigation.

In summary, PTMs function as an integrated network rather than in isolation. Accordingly, interventions directed at a single writer/eraser enzyme may propagate network-level effects, unintentionally rewiring other PTMs on shared substrates. Mapping these interactions is therefore critical for designing safer, more effective PTM-targeted therapies in ARDS.

Therapeutic potential: targeting PTMs for ARDS treatment

Translating PTM mechanisms to clinical ARDS therapeutics remains the “last mile”, as preclinical models demonstrate potential in modulating PTMs to attenuate lung injury, yet clinical translation is hindered by syndrome heterogeneity and signaling pathway essentiality. To bridge this gap, strategies are shifting from broad-spectrum immunosuppression to precision medicine, aiming to selectively reverse key pathological “switches” identified in “Phosphorylation: the master switch in ARDS signaling”, “Ubiquitination and deubiquitination: regulating protein stability”, “Acetylation: epigenetic and metabolic regulation”, “Emerging PTMs and crosstalk in ARDS”, and “Metabolite-driven regulation of the PTM landscape in ARDS” sections. Here, we classify agents by evidence stage, specifically into late-stage or approved with clinical data, mid-stage preclinical, and early-concept categories, while critically assessing key translational barriers such as patient heterogeneity and off-target effects.

Despite strong mechanistic rationale, clinical translation of PTM-targeted therapies in ARDS remains limited by context-dependent PTM functions that may simultaneously affect injurious and reparative processes, temporal heterogeneity complicating therapeutic timing, and cellular heterogeneity reducing the efficacy of non-cell-specific interventions. Figure 3 summarizes representative PTM-targeting agents, their molecular targets, and current research stages, providing a translational roadmap for PTM-based therapeutic development in ARDS.

Figure 3 Therapeutic strategies targeting PTMs in ARDS: representative agents and research stages. Agents are organized by targeted PTM type (rows) and research maturity (columns, from clinical evidence to early concept). Each entry lists the molecular target and mechanism. Symbols indicate trial status: green checkmark, positive result; red cross, negative/neutral; orange circle, ongoing; purple double ring, mixed/partial evidence; black circle, preclinical only; red triangle, terminated/safety concern. Dashed connectors denote dual-PTM mechanisms or potential combinations. ARDS, acute respiratory distress syndrome; PTM, post-translational modification.

Late-stage agents: a critical re-evaluation of clinical evidence

For drugs already approved for other indications or in advanced trials, repurposing offers a faster path, but ARDS studies have yielded mixed results due to patient heterogeneity and timing issues.

In kinase modulation, agents targeting the JAK-STAT pathway, including baricitinib (a direct JAK inhibitor) (188,189) and tocilizumab (IL-6 receptor antagonist) (190,191), have shown modest mortality reduction in severe COVID-19-related ARDS through large platform trials such as ACTT-2, RECOVERY, and REMAP-CAP. However, in non-COVID ARDS, evidence remains limited to small observational studies and consensus discussions, with no large dedicated RCTs to date confirming efficacy; both agents raise concerns over immunosuppression risks and secondary infections in heterogeneous phenotypes (192). Similarly, Simvastatin, which inhibits NF-κB in preclinical models (193,194), failed to improve survival in the HARP-2 trial overall; subgroup analyses in hyperinflammatory phenotypes suggest potential benefit but require prospective validation (195). Statins like rosuvastatin, similar to simvastatin, failed to show overall benefit and showed trends toward hepatic and renal dysfunction in the SAILS trial for sepsis-associated ARDS (196). Weak subgroup analyses suggest potential in hyperinflammatory phenotypes but warrant caution and further validation due to their post-hoc nature. For neutrophil elastase/JNK/NF-κB inhibition, sivelestat is in an ongoing phase III trial (NCT04973670), with protocol published but final results pending; earlier trials showed mixed outcomes, highlighting translational challenges (197). Dapagliflozin, an SGLT2 inhibitor linking metabolism to inflammation, showed no significant benefit for organ dysfunction or death in DARE-19 subgroup analyses (198).

Additionally, corticosteroids such as dexamethasone modulate NF-κB signaling and have shown survival benefits in moderate-to-severe ARDS via the RECOVERY (COVID-specific) and DEXA-ARDS trials, though optimal timing and dosing remain debated due to risks of immunosuppression and delayed viral clearance (199,200).

For ubiquitin modulators, maresin1 inhibits ENaC/Na, K-ATPase ubiquitination to promote fluid clearance in animal models (201), but human trials are lacking. Overall, these agents highlight the need for phenotype-specific trials to address translational gaps.

Mid-stage candidates: preclinical promise with emerging data

Agents targeting emerging PTMs show preliminary evidence in animal models, but require phase I/II validation.

For E3 ligases, BC-1215 inhibits FBXO3 to preserve anti-inflammatory proteins (71,202), and ginsenoside Rg1 reduces FBXO3 via m6A-YTHDF1, protecting PGC-1α in rodent ARDS (203); both lack clinical data. DUB modulators like sulbactam downregulate USP22 to degrade viral proteins in COVID-ARDS models (204), while OTUD1 deficiency mitigates IFN-γ/STAT1 and TNF-α/NF-κB in preclinical sepsis (205), but human relevance is unproven.

Epigenetic modulators, such as HDAC inhibitors, like valproic acid and vorinostat, suppress NETs and activate Nrf2/HO-1 in models (206,207), yet broad effects raise immunosuppression concerns without ARDS-specific RCTs (100,102). AMPK activators like metformin restore mitochondrial homeostasis and inhibit mTOR/TGF-β (96,208), with meta-analyses supporting reduced inflammation in preclinical ARDS, but large trials are needed. Additionally, naturally derived MAPK modulators such as arctigenin (209), daphnetin (210) and andrographolide (211) have shown preclinical efficacy in suppressing MAPK/NF-κB in LPS-ALI models, yet remain preclinical with no human ARDS data, limited by delivery challenges and potential toxicity in heterogeneous patients. JAK inhibitors like ruxolitinib (212) and tofacitinib (213) demonstrate feasibility in COVID-ARDS but lack dedicated non-COVID RCTs, underscoring heterogeneity-related translational gaps and the need for further investigation in broader ARDS phenotypes.

For non-canonical PTMs, PAD4 inhibitors, like Cl-amidine, GSK484, block citrullination and NETosis in murine models (214-217), potentially synergizing with DNase I (218). SDH activators like dimethyl malonate reverse succinylation in lung injury (16), and OGT inhibitors (OSMI-1) dampen NF-κB O-GlcNAcylation (156), but all remain at animal stage, limited by off-target effects.

Early-concept approaches: theoretical potential and challenges

Innovative technologies like PROTACs enable targeted degradation of pathological proteins including hyperactive kinases or E3 ligases, offering durable resolution over inhibition. Nanocarriers improve site-specific delivery, minimizing systemic toxicity in inflamed lungs (219). Metabolic reprogramming via MRRGs provides pathogenic insights for precision targeting (220). However, these are conceptual, with no dedicated ARDS trials; challenges include scalability, safety, and addressing ARDS heterogeneity through multi-omics subphenotyping (221). Future directions emphasize integrating these with biomarker-guided strategies to overcome these hurdles.

Conclusions

PTMs orchestrate the molecular pathogenesis of ARDS by modulating cellular signaling and functional responses. The interplay between phosphorylation-driven cytokine cascades, ubiquitin-mediated protein turnover, and metabolic–epigenetic reprogramming governs disease trajectory. Deciphering this “PTM code” from histone citrullination to mitochondrial succinylation, provides insight into how dysregulated PTM networks may contribute to alveolar barrier dysfunction and progression from reversible injury to fibrosis.

Clinical translation remains challenging. Broad-spectrum kinase inhibition can compromise host defense and may induce off-target toxicity. Additionally, the complex pulmonary microenvironment can limit effective drug delivery to target cells. Achieving therapeutic efficacy requires precision: developing isoform-selective modulators and employing endothelial-targeted delivery systems to concentrate interventions at sites of injury, attenuating pathological signaling while preserving systemic immune function.

Future therapeutics will likely depend on integrating multi-omics with precision medicine. High-resolution phosphoproteomics and metabolomics can define patient-specific PTM signatures, facilitating a shift from syndromic management to molecularly guided therapy. These approaches can support dynamic risk stratification and the deployment of emerging modalities, including PROTACs and mRNA-based therapeutics, to reprogram pathological networks and translate molecular insights into patient-specific therapies.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0684/prf

Funding: This work was supported by Young Experts of Taishan Scholars (No. tsqn202211380); the China Postdoctoral Science Foundation (No. 2023M741864); the Health Science and Technology Innovation Team Construction Project of Shandong Province; and the Medical and Health Technology Project of Shandong Province (No. 202318001632).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0684/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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