Acute lung injury (ALI) is characterized as an acute, diffuse inflammatory condition of the lungs, precipitated by a variety of intra- and extra-pulmonary pathogenic factors of non-cardiogenic origin. This condition can lead to severe hypoxemia and acute respiratory failure, potentially progressing to the critical illness, known as acute respiratory distress syndrome (ARDS). The reprogramming of glucose metabolism is intricately associated with immune responses and inflammatory processes. Study indicates that sepsis link to hyperlactatemia; during septic ALI, macrophages recruited and activated by lipopolysaccharides (LPS) exhibit enhanced glycolysis, which further exacerbates the inflammatory response and worsens oxidative stress, leading to progression of ALI and potentially ARDS or even death, suggesting that glycolytic inhibition is a potent anti-inflammatory strategy for the treatment of ALI [1]. ARDS is a critical respiratory condition characterized by an unclear pathogenesis, a lack of effective pharmacological treatments, and a low quality of life and survival rate for affected individuals. Currently, the incidence of new ALI cases worldwide exceeds three million annually, with clinical meta-analyses revealing a mortality rate of 43%. Furthermore, up to 50% of survivors experience significant pulmonary dysfunction. Persistent inflammation, coupled with the loss of vascular barrier integrity, results in pulmonary edema and multiorgan dysfunction, which are significant contributors to the elevated mortality associated with ALI and ARDS. The pulmonary vascular system, due to its extensive surface area, is particularly susceptible to the activation of inflammatory responses. In the context of ALI, the infiltration of inflammatory cells and the release of inflammatory mediators, along with increased tissue metabolic activity, lead to a heightened demand for oxygen. Additionally, inflammation-induced vasoconstriction further diminishes oxygen supply to the affected regions of the lung, resulting in hypoxemia. This hypoxic state subsequently triggers the overexpression of HIF, which directly promotes the upregulation of LDHA and the degradation of Inhibitor of kappa B zeta (I$\kappa$B-$\zeta$). These molecular changes contribute to the reprogramming of cellular metabolism and the exacerbation of inflammatory responses.

Vascular endothelial cells (VECs) constitute a layer of mononuclear cells situated between the bloodstream and the vascular wall tissues. These cells are capable of secreting a variety of vasoactive substances through autocrine, endocrine, and paracrine mechanisms, thereby playing crucial roles in regulating vascular tone, inhibiting the proliferation of smooth muscle cells, and modulating inflammatory responses within the vascular wall. The structural and functional integrity of VECs is essential for the maintenance of vascular wall function and lung homeostasis. Under homeostatic conditions, VECs remain quiescent and exhibit antioxidant and anti-inflammatory properties. However, during inflammatory events, VECs participate in the interplay between local and systemic immune responses and serve as significant targets for inflammatory processes. This involvement can enhance innate immune responses through the production and release of cytokines and chemokines, including the activation of the NF-$\kappa$B signaling pathway and the pro-inflammatory factors interleukin-6 (IL-6) and interleukin-8 (IL-8). The expression of pro-inflammatory factors such as IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) can be activated, positioning VECs as a secondary a cascade of chain reactions in response to inflammation [2].

VECs are influenced by various factors that prompt them to lose their original characteristics and undergo significant alterations in polarity, morphology, and function. This process leads to their transformation into mesenchymal cells, such as fibroblasts and smooth muscle cells, a phenomenon known as endothelial-to-mesenchymal transition (EndMT) [3]. Pyruvate dehydrogenase kinase (PDK) phosphorylates pyruvate dehydrogenase complex (PDH) during EndMT, which inhibits the mitochondrial catabolism of pyruvate in endothelial cells, resulting in the reduction of endothelial pyruvate by lactate dehydrogenase (LDH) reduces pyruvate from endothelial cells to lactate, resulting in a paradigm shift in the energy metabolism of VECs.

Abnormal communication between VECs and VSMCs is a critical factor in the initiation and progression of vasculopathic alterations. In ALI, lung epithelial cells and vascular endothelial cells leads to diffuse interstitial and alveolar edema, progressive hypoxemia, and respiratory distress, which subsequently triggers hypoxic pulmonary vasoconstriction (HPV) [4]. Although early HPV is a protective immune response, persistent inflammation and hypoxia can result in the hyperproliferation of VSMCs, thickening of the vascular wall, and ultimately the development of ARDS. Nitric oxide and carbon monoxide in VECs indirectly induce vasodilation and modulate the inflammatory response through crosstalk between VECs and VSMCs, while also promoting the proliferation and migration of VSMCs. The knockdown of vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23) in endothelial cells has been shown to inhibit the proliferation, migration, and phenotypic transformation of smooth muscle cells co-cultured with endothelial cells. Furthermore, microRNA-126-3p secreted by endothelial cells enhances the proliferation and dedifferentiated phenotype of smooth muscle cells, contributing to the thickening of the neointima in arterial vessels in murine models [5].

VSMCs are a highly differentiated cell type characterized by the expression of various proteins associated with vascular contraction, including smooth muscle myosin heavy chain (SMMHC) and alpha-smooth muscle actin ($\alpha$-SMA). In their physiological state, VSMCs are referred to as contractile VSMCs, which constitute approximately 90% of the vascular mesenchymal layer and exhibit low capacities for proliferation, migration, and secretion. Despite their high level of differentiation, VSMCs are not terminally differentiated and retain significant phenotypic plasticity. In response to inflammatory stimuli, there is a noted decrease in the expression of contractile phenotypic proteins and an increase in the expression of secretory phenotypic proteins, such as Kruppel-like factor 4 (KLF4) and Osteopontin (OPN). Consequently, these cells are classified as secretory (synthetic) VSMCs, which do not participate in vasoconstriction but instead play a role in regulating vascular remodeling [6]. It also secretes a variety of inflammatory factors, such as interleukins (ILs), tumor necrosis factor-$\alpha$ (TNF-$\alpha$), and monocyte chemotactic protein-1 (MCP-1).

During vascular injury, VSMCs migrate from the mesentery to the intima in response to growth factors secreted by endothelial cells, resulting in intimal hyperplasia and restenosis. To mitigate excessive proliferation, nitric oxide (NO) and prostacyclin (PGI2) released by endothelial cells inhibit the over-proliferation and migration of VSMCs, thereby maintaining the stability of the vessel wall. Furthermore, VSMCs may undergo phenotypic transformation, adopting a myofibroblast-like phenotype that is more conducive to tissue repair, characterized by enhanced proliferation and increased secretion of extracellular matrix (ECM). Consequently, investigating the interactions between vascular smooth muscle cells and vascular endothelial cells in the context of inflammatory responses and cell proliferation during the development of ALI is an effective way to ameliorate the adverse prognosis associated with ALI and to prevent vessel wall thickening.

Energy metabolism serves as a crucial regulator of cellular function and is significantly altered when tissues and cells experience pathological changes. Under normal physiological conditions, cells are efficiently supplied with adenosine triphosphate (ATP) through glycolysis and oxidative phosphorylation. One molecule of glucose can yield a net production of 36 ATP molecules, which provide the necessary energy for various cellular activities. In hypoxic conditions, cells are unable to utilize oxidative phosphorylation effectively for ATP production; instead, they resort to aerobic glycolysis facilitated by M2-type pyruvate kinase (PKM2) and LDHA, resulting in a net production of only 2 ATP molecules. Concurrently, LDHA sustains aerobic glycolysis by regenerating NAD⁺ from NADH. Although aerobic glycolysis is less efficient, it occurs at a rate that is approximately 100 times faster than oxidative phosphorylation, thereby meeting the short-term energy demands of the cell in the absence of adequate oxygen, albeit at the cost of increased glucose consumption and lactate production. Notably, certain cell types, including activated immune cells, tumor cells, and infected cells, adopt an aerobic glycolytic pathway to convert glucose to lactate even under normoxic conditions. This metabolic shift signifies a change in cellular function and signaling pathways and is commonly referred to as the Warburg effect [21].

Acute injury leads to an insufficient supply of oxygen to lung tissue, prompting VSMCs to depend primarily on LDHA-mediated glycolysis for energy production, rather than on mitochondrial oxidative phosphorylation. This metabolic reprogramming represents a crucial adaptive mechanism for VSMCs to manage oxidative stress and inflammation. In conditions of hypoxia, hypoxia-inducible factor 1 alpha (HIF1$\alpha$) exhibits sensitivity to fluctuations in oxygen levels and serves as the active subunit of the HIF. Under hypoxic conditions, HIF-1$\alpha$ becomes more stable and, upon translocating to the nucleus, it dimerizes with the oxygen-independent HIF-1$\beta$/ARNT to initiate the expression of downstream target genes. However, the lactate-mediated response to sustained hypoxia appears to be functionally independent of HIF-1$\alpha$, as it involves the NDRG family member 3 (NDRG3) [22]. Similar to HIF1$\alpha$, NDRG3 undergoes degradation in a prolyl hydroxylase domain 2 (PHD2)/von Hippel-Lindau (VHL)-dependent manner under normoxic conditions. However, during prolonged hypoxia, NDRG3 is protected from degradation through its binding to lactate. The resultant increase in NDRG3 levels, independent of HIF1$\alpha$, activates the RAF-ERK signaling pathway, which regulates hypoxia-related pathophysiological responses, including inflammation and angiogenesis. Furthermore, both pharmacological and genetic inhibition of LDHA restricts NDRG3 protein accumulation in a dose-dependent manner. Lactate is capable of reversing these effects without influencing HIF1$\alpha$ protein levels. Recent studies have identified endogenous branched-chain $\alpha$-keto acids (BCKAs) as newly discovered inhibitors of PHD2, which aerobically activate HIF1$\alpha$ signaling in normal VSMCs. This process involves a positive feedback loop in which BCKAs stimulate HIF1$\alpha$, leading to increased expression of LDHA. The resultant production of lactate is anticipated to lower cellular pH, thereby enhancing the production of L-2-hydroxyglutarate (L2HG), which subsequently inhibits PHD2 activity. This inhibition further amplifies HIF1$\alpha$ activity under aerobic conditions. HIF1$\alpha$ plays a unique and complex role in regulating VSMC function across various vascular beds. Specifically, BCKAs inhibit PHD2 activity, activate HIF1$\alpha$ signaling, enhance glycolytic activity, and facilitate the transition of pulmonary arterial smooth muscle cells (PASMCs) to a synthetic phenotype. Collectively, these mechanisms contribute to vascular dysfunction, including the development of pulmonary arterial hypertension (PAH) [23, 24].

Research has demonstrated that the supplementation of lactate in growth medium enhances the synthetic phenotype of VSMCs derived from human induced pluripotent stem cells [25]. Furthermore, lactate promotes the polarization of alternatively activated macrophages exhibiting an anti-inflammatory (M2-like) phenotype. These macrophages play a crucial role in angiogenesis and tissue remodeling, as well as stimulating the release of vascular endothelial growth factor from endothelial cells, thereby facilitating wound healing and tumor-associated angiogenesis [26, 27, 28, 29].

The etiology of ALI is multifaceted, resulting in damage to alveolar epithelial cells and vascular endothelial cells. This condition triggers an inflammatory response and induces persistent hypoxemia, ultimately leading to the development of ARDS, and the high mortality associated with ALI has garnered significant attention within the medical community. LDHA is a crucial metabolic enzyme that regulates hypoxemia during the progression of ALI. It induces alterations in the energy metabolism of VSMCs and provides energy for cellular proliferation and differentiation through aerobic glycolysis. Additionally, LDHA promotes the repair of damaged tissues, vasoconstriction, endothelial-mesenchymal transition, cell proliferation, and migration, while also generating reactive oxygen species that further exacerbate inflammatory responses. LDHA serves not only as an enzyme involved in energy metabolism but also as a protein factor that regulates various biological processes. It is recognized as an important biomarker and potential therapeutic target for ALI, ARDS, tumor development, and poor prognosis. Consequently, comprehensive research into the pro-inflammatory and metabolic functions of LDHA, along with the identification of novel genes that synergistically interact with LDHA, will significantly enhance the foundational theoretical understanding of ALI pathogenesis.

Numerous studies have substantiated the efficacy of various LDHA inhibitors in models of lung injury and tumors. FX11, a competitive inhibitor of NADH, has been shown to reduce bacterial load and inhibit necrotic lesions in the lungs of tuberculosis-infected mice by impeding glycolysis [40]. Furthermore, its nanocarrier formulation (FX11@TPEG-WS₂) targets mitochondria and enhances antitumor efficacy when used in conjunction with acoustic kinetic therapy [41]. In combination with metformin, FX11 activates the AMPK$\alpha$ axis, thereby inducing apoptosis in pancreatic cancer cells [42]. Dihydropyrimidine derivative 14 (GNE-140) demonstrated significant inhibitory activity against human lactate dehydrogenase A (hLDHA) within the low micromolar range (IC₅₀ = 0.48 µM) [43]. It effectively blocked glycolysis-dependent histone lactylation (H3K18la) in a model of PM2.5-induced pulmonary fibrosis, down-regulated the TGF-$\beta$/Smad2/3 (Mothers Against Decapentaplegic Homolog 2/3) and VEGFA (Vascular Endothelial Growth Factor A)/ERK signaling pathways, and mitigated inflammation and fibrosis [44]. Additionally, N-hydroxyindole derivatives (NHI-Glc-2), in conjunction with PDK1 (3-Phosphoinositide-Dependent Protein Kinase-1) inhibitors, facilitate metabolic reprogramming of lung adenocarcinoma from glycolysis to oxidative phosphorylation by targeting critical nodes of glycolysis, thereby synergistically inhibiting the AKT (AKT Serine/Threonine Kinase)/mTOR and RAS (Rat Sarcoma virus oncogene homolog)/ERK pathways [45]. Furthermore, oxaloacetate, a competitor at the pyruvate site, enhances CD8⁺ T-cell infiltration in a non-small cell lung cancer (NSCLC) model [43]. Cotton-phenol derivatives exhibit non-selective inhibition of LDH and reduce collagen deposition in bleomycin-induced lung fibrosis [43]. Natural products such as curcumin and gallocatechin gallate (EGCG) have emerged as promising drug candidates showing efficacy as LDHA inhibitors and in overcoming EGFR-TKI resistance, especially in cancer therapy [46]. Despite the demonstrated efficacy of these compounds in preclinical models, no LDHA inhibitors have progressed to clinical trials. This limitation is primarily attributed to issues related to target selectivity, pharmacokinetic deficiencies, and toxicity risks. Therefore, structural optimization strategies, such as the nanocarrierization of FX11 [41], along with combination therapy approaches, are essential to enhance the translational potential of these compounds.

The comprehensive investigation of the LDHA regulatory network is crucial for addressing the challenges associated with clinical translation. Clarifying the role of LDHA in modulating endothelial inflammation and permeability via the lactate-NF-$\kappa$B/STAT3 axis [47], in conjunction with spatial metabolomics, is expected to significantly enhance our understanding of endothelial-vascular smooth muscle interactions in ALI. Moreover, examining the interaction between LDHA and cyclic GMP-AMP synthase (cGAS)-STING, particularly the mechanism by which FX11 induces cGAS to bolster anti-tumor immunity, as well as its association with the human tumor suppressor FLCN (Folliculin), will provide valuable insights into the regulation of glycolysis and mitochondrial metabolic transitions [43, 48]. This exploration aims to elucidate the mechanisms underlying the interplay between metabolism and immunity. We propose the development of humanized lung-like organoids and the application of a single-cell multi-omics platform to investigate the cell-specific effects of LDHA on macrophage polarization, epithelial-mesenchymal transition (EMT), and T-cell depletion [44, 49]. Inhibition of LDHA has been demonstrated to modulate the reactive oxygen species (ROS)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) and HIF-1$\alpha$ signaling networks, thereby facilitating the formulation of synergistic strategies in conjunction with immunotherapeutics, such as anti-PD-1 (Programmed Cell Death Protein 1) agents, or epigenetic drugs, including histone deacetylase (HDAC) inhibitors [42, 43, 45, 49]. Furthermore, we aim to optimize these combinations by designing dual-targeted inhibitors that concurrently target LDHA and pyruvate kinase M2 (PKM2) to mitigate metabolic compensation [46]. Additionally, we will develop lung-targeted smart delivery systems, such as glutathione-responsive vesicles [50], and identify synthetic lethal targets through CRISPR screening. This research presents a novel framework for metabolic-immune interventions in the context of lung diseases.

ALI represents a critical inflammatory disorder characterized by elevated mortality rates, primarily resulting from dysregulated metabolism in VSMCs and sustained inflammatory responses. This review aims to clarify the significant function of LDHA in the metabolic reprogramming of VSMCs and the enhancement of inflammatory processes during ALI. In the context of hypoxia and inflammation, LDHA expression is increased through the HIF-1$\alpha$ signaling pathway, thereby facilitating the Warburg effect. This metabolic alteration not only supports ATP generation but also intensifies inflammation through two distinct mechanisms. Firstly, LDHA directly contributes to oxidative stress via the interaction between NADH and LDHA, activates NF-$\kappa$B/STAT3 signaling pathways, and destabilizes I$\kappa$B-$\zeta$, which leads to an increased release of pro-inflammatory cytokines such as IL-6 and TNF-$\alpha$. Secondly, lactate produced by LDHA indirectly exacerbates inflammation by inhibiting immune cell functionality, promoting IL-17 secretion in CD4⁺ T cells, and driving macrophage polarization towards pro-inflammatory phenotypes. Experimental approaches to inhibit LDHA, such as the use of FX11, have demonstrated a reduction in lung edema, neutrophil infiltration, and lactate levels, underscoring its potential as a therapeutic target. Additionally, post-translational modifications of LDHA, including crotonylation and ubiquitination, further influence VSMC proliferation, migration, and vascular remodeling. Despite encouraging results from preclinical studies, the translation of LDHA inhibitors into clinical practice faces challenges related to selectivity and toxicity. Future investigations should prioritize the optimization of LDHA-targeted therapies through the use of nanocarrier delivery systems, dual-target inhibitors (e.g., LDHA/PKM2), and combinatorial approach has with immunotherapies. Furthermore, employing multi-omics strategies to investigate LDHA’s role in metabolic-immune interactions and vascular-endothelial dynamics will enhance our comprehension of ALI pathogenesis and facilitate the development of innovative interventions to address this life-threatening condition.

DL and XLF contributed equally to the study design, data analysis, literature search, and preparation of the initial draft of the manuscript. LXX was responsible for the study conception and supervision, while LXX and SLD were involved in the design, editing, and revision of the manuscript. All authors have approved the final version of the manuscript and have participated sufficiently in the work, thereby agreeing to be accountable for all aspects of the research.

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This research received funding from China NSFC Key Grant (82341119).

The authors declare no conflict of interest.