NDRG1 as a sensor and mediator of endothelial stress: from homeostasis to inflammation and cardiovascular disease

Abstract

N-myc downstream-regulated gene 1 (NDRG1) is a multifunctional, stress-responsive protein with pleiotropic roles across diverse cell types. Although extensively studied in cancer, recent evidence points to its emerging, context-dependent functions in vascular endothelial cells. In this mini-review, we synthesize current knowledge on the regulation of NDRG1 under environmental stressors, such as hypoxia, inflammation, disturbed shear stress and heavy metal (iron, nickel, copper and cobalt) and its impact on endothelial homeostasis. We highlight NDRG1’s involvement in key processes including vascular inflammation, thrombosis, permeability and remodeling. Drawing parallels with its dualistic role in tumor biology, we propose that NDRG1 acts as a dynamic integrator of environmental cues in the endothelium, orchestrating adaptive or maladaptive responses depending on microenvironmental context. These insights support a broader conceptual framework positioning NDRG1 as a potential biomarker and therapeutic target in cardiovascular disease.

Introduction

Adaptation to vascular and tissue demands depends on the dynamic activity of the endothelium, a monolayer of highly specialized endothelial cells (ECs) forming the critical interface between blood and the vessel wall. Once viewed primarily as a passive barrier, the endothelium is now recognized as a highly dynamic environments and central regulator of vascular homeostasis. By continuously sensing and integrating cues from the extracellular environment, ECs orchestrate a range of essential functions, including modulation of vascular tone, hemostatic balance, selective permeability, leukocyte trafficking and angiogenesis [1].

This finely tuned endothelial equilibrium is acutely sensitive to perturbations in hemodynamic forces and circulating mediators. Under environmental stresses, including hypoxia, inflammation, disturbed shear stress and metabolic stress, ECs undergo a phenotypic transition toward pro-inflammatory, pro-thrombotic and pro-remodeling states [2, 3]. Indeed, these changes mark the onset of endothelial dysfunction, a pivotal early event in the pathogenesis of cardiovascular diseases (CVDs) such as atherosclerosis, hypertension, coronary artery disease and ischemia–reperfusion injury [1, 4, 5]. This dysfunctional state is characterized by increased vascular permeability, metabolic reprogramming, mitochondrial remodeling, impaired nitric oxide (NO) signaling and activation of stress-response pathways that govern EC survival, apoptosis and angiogenesis [6] (Fig. 1A).

Fig. 1.

Endothelial dysfunction as a central driver of cardiovascular disease. (A) The vascular endothelium dynamically integrates extracellular cues to regulate vascular tone, hemostasis, permeability, leukocyte trafficking, and angiogenesis. Environmental stressors—including hypoxia, inflammation, disturbed shear stress, and metabolic imbalance—disrupt this homeostasis, triggering endothelial dysfunction characterized by mitochondrial remodeling, nitric oxide dysregulation, metabolic reprogramming, and vascular leakage. These maladaptive responses contribute to the progression of cardiovascular diseases such as atherosclerosis, hypertension, coronary artery disease, and ischemia-reperfusion injury. (B) NDRG1 is a 394-amino acid protein containing an N-terminal helix-turn-helix (HTH) motif, an α/β hydrolase core with a phosphopantetheine attachment site (PPAS) and CAP-like domain, and a C-terminal region harboring three tandem decapeptide repeats. It includes multiple phosphorylation sites (Ser328, Ser330, Ser346, Ser356, and Ser366), and functions as a context-dependent regulator of stress responses in endothelial cells

Despite substantial advances in endothelial biology, the molecular pathways that detect, interpret and respond to external perturbations remain incompletely understood. Elucidating these mechanisms is essential for developing targeted strategies to preserve or restore endothelial integrity in the face of environmental and hemodynamic stress. Among the emerging regulators within this network, N-myc downstream-regulated gene 1 (NDRG1) has recently gained attention as a context-sensitive mediator of vascular adaptation to stress. Initially studied in cancer biology, where it functions either as a metastasis suppressor or, in some contexts, as an oncogene [7, 8], NDRG1 is now increasingly implicated in vascular remodeling, angiogenesis, inflammation and thrombosis [9, 10]. These findings suggest that NDRG1 may act as a molecular integrator of environmental stress signals in the endothelium, orchestrating adaptive or maladaptive responses depending on the physiological or pathological context.

NDRG1 (formerly known as CAP43, DRG1, PROXY1, Rit42, RTP and TDD5) encodes a 43-kDa protein of the highly conserved NDRG family (NDRG1–4). It is ubiquitously expressed and displays context-dependent subcellular localization, dynamically shuttling between the cytoplasm, perinuclear region, nucleus and plasma membrane in response to extracellular cues [11]. Structurally, NDRG1 possesses an α/β hydrolase fold, multiple phosphorylation sites, and a serine/threonine-rich C-terminal domain that enables protein–protein interactions (Fig. 1B). Although it lacks intrinsic enzymatic activity, NDRG1 acts as a scaffold for signaling complexes involved in regulating cell proliferation, apoptosis, migration, lipid metabolism and immune responses.

In ECs, NDRG1 expression is acutely responsive to pathophysiological stimuli including hypoxia, inflammatory cytokines, disturbed shear stress, metal ions such as iron, and metabolic imbalances, conditions closely linked to vascular disease. Emerging evidence suggests that NDRG1 may exert both protective and deleterious effects on endothelial function, depending on the microenvironmental context and temporal dynamics of its expression. However, the precise molecular mechanisms underlying its dualistic role remain poorly understood.

While extensive experimental and clinical evidence has firmly established that stress-induced endothelial activation is a key initiating and driving factor in the development of vascular pathology, this mini-review focuses specifically on synthesizing current knowledge regarding NDRG1’s function in vascular endothelial biology, with an emphasis on its regulation under stress conditions and its contribution to endothelial dysfunction in cardiovascular disease. By integrating recent mechanistic insights, we aim to highlight NDRG1’s emerging role as a modulator of endothelial homeostasis and a potential therapeutic target. We hope this review not only consolidates experimental evidence linking endothelial inflammation to vascular pathology but also offers a conceptual framework for future clinical investigations and guides the development of targeted therapies for CVD.

NDRG1 and the hypoxic reprogramming of endothelial cells

Adequate oxygen supply is essential for tissue homeostasis, and its reduction, whether systemic (e.g. anemia) or local (e.g. atherosclerosis, stroke), rapidly disrupts endothelial integrity and function. ECs, as frontline sensors of oxygen fluctuations, initiate early adaptive responses to hypoxia [12]. Interestingly, a notable feature of EC biology is their reliance on glycolysis for > 85% of ATP production, despite direct contact with oxygenated blood [13, 14]). This “glycolysis addiction” is thought to limit mitochondrial reactive oxygen species (ROS) generation, preserve oxygen for perivascular tissues, and enable rapid ATP production to support barrier maintenance, migration, and sprouting angiogenesis [14, 15]. Consequently, ECs can tolerate hypoxia relatively well as long as glucose is available to sustain glycolysis,under these conditions, hypoxia’s impact on non-glycolytic pathways, such as redox homeostasis, mitochondrial dynamics and angiogenic signaling, often plays a more decisive role in determining endothelial fate. These effects ultimately lead to a complex phenotypic reprogramming of ECs, characterized by pro-inflammatory activation, dysregulated mitochondrial dynamics, and enhanced angiogenic signaling, which together define the core features of endothelial dysfunction [12].

Among the most rapidly induced genes under hypoxic stress, NDRG1 has emerged as a key mediator of vascular adaptation to oxygen deprivation [10, 16]. Its transcriptional activation is principally governed by hypoxia-inducible factor-1α (HIF-1α), which binds two functional hypoxia-response elements (HREs) in the NDRG1 promoter [7]. Additional transcriptional regulators, including Egr-1, Sp1, YB-1, Smad7 and KLF4, further modulate NDRG1 expression in a cell type–specific manner, reflecting the context-dependent nature of its regulation [17–19]. In addition to transcriptional regulation, NDRG1 expression under hypoxia is modulated by post-translational modifications, such as phosphorylation, which influence its subcellular localization and interaction with other proteins [20]. Its induction is both time- and oxygen concentration-dependent [10, 18], and is frequently associated with nuclear translocation, where it contributes to transcriptional and metabolic reprogramming [7, 21]. These regulatory mechanisms highlight NDRG1 as a finely tuned effector within the hypoxic signaling cascade (Fig. 2).

Fig. 2.

NDRG1 integrates hypoxic signaling in endothelial cells. (A) Under hypoxia, hypoxia-inducible factor 1-α (HIF-1α) is stabilized and translocated into the nucleus, where it associates with HIF-1β to form the HIF-1 complex. This complex binds to the hypoxia response element (HRE) located in the promoter region of the NDRG1 gene, thereby inducing its transcription. ((B) NDRG1 contributes to cell survival by increasing the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, which inhibit mitochondrial fission, block cytochrome C release, and prevent caspase activation. NDRG1 can also promote apoptosis via a p53-dependent pathway. (C) In response to decreased oxygen, which inhibits oxidative phosphorylation, NDRG1 supports ATP production by increasing glucose and lactate uptake, thereby contributing to the metabolic adaptation of endothelial cells to hypoxia. (D) NDRG1 stimulates cell proliferation and migration through the KLF4/NDRG1/DRP1 axis. It interacts with the RNA-binding protein TF15, promoting its cellular localization, and activates several signaling pathways, including PI3K/Akt, p53, and HIF-1α. HIF-1α induces the transcription of VEGF, a key factor in angiogenesis

Although initially characterized in cancer, mechanistic insights into NDRG1’s role in hypoxia, particularly can be directly translated to the vascular context. In hypoxic hepatocellular carcinoma cells (HCC), NDRG1 promotes survival by stabilizing mitochondrial integrity and repressing apoptosis [22]. Mechanistically, it inhibits mitochondrial fission, thereby preserving mitochondrial membrane potential and preventing cytochrome c release. Loss of NDRG1 leads to increased pro-apoptotic proteins (e.g., BAX), decreased anti-apoptotic markers (e.g., Bcl-2, Bcl-xL), and caspase activation, collectively reflecting mitochondrial dysfunction [22]. Although this pro-survival role may confer resistance to apoptosis in cancer, NDRG1 has also been shown to promote p53-dependent cell death in human colorectal adenocarcinoma [23], highlighting its context-dependent function. These roles are particularly relevant in ECs, where tight regulation of mitochondrial dynamics under hypoxia is essential for determining cell fate and maintaining vascular integrity [24].

In parallel, NDRG1 supports metabolic adaptation to hypoxia [22, 25]. In both cancer and activated endothelial cells [25, 26]. NDRG1 promotes glucose uptake and lactate production, thereby sustaining ATP generation when oxidative phosphorylation is compromised [22]. Mechanistic work in HCC cells shows that NDRG1 loss reduces glycolytic flux and extracellular acidification, highlighting its function in sustaining energy metabolism during stress [22]. These functions are particularly pertinent in ECs, which already rely heavily on glycolysis in normoxia to limit mitochondrial ROS production and preserve oxygen for surrounding tissues [13, 14]. By reinforcing this glycolytic program under hypoxia, NDRG1 may help preserve endothelial viability and function, while also influencing angiogenic activation and inflammatory signaling [26]. Moreover, the glycolytic program in ECs is tightly controlled by transcriptional regulators such as c-MYC, which enhances expression of glucose transporters and glycolytic enzymes and is essential for angiogenesis [27, 28]. Although direct vascular evidence is limited, NDRG1’s reported ability to stabilize c-MYC [29] suggests a potential mechanism for amplifying c-MYC–driven glycolytic reprogramming under hypoxic stress.

Consistent with this, in human pulmonary artery endothelial cells (HPAECs), hypoxia robustly induces NDRG1 expression [10]. Functionally, NDRG1 drives endothelial proliferation, migration, and tube formation, phenotypes associated with vascular remodeling and pathological angiogenesis. Silencing NDRG1 reverses these changes and reduces mitochondrial fission via the KLF4/NDRG1/DRP1 axis [16]. Beyond acting as a downstream target of HIF-1α, NDRG1 also serves as a feedforward amplifier of hypoxic signaling via its interaction with the RNA-binding protein TAF15, which facilitates TAF15 nuclear localization and activates downstream pathways including PI3K/Akt, p53 and HIF-1α itself, thereby reinforcing the hypoxic response [10, 30].

HIF-1α, in turn, induces the transcription of vascular endothelial growth factor (VEGF), a central mediator of hypoxia-driven neovascularization [31]. Interestingly, NDRG1 expression positively correlates with VEGF levels and actively contributes to VEGF-induced angiogenesis by enhancing PLCγ1/ERK signaling, a key pathway regulating endothelial cell proliferation and migration [32, 33]. Notably, this pro-angiogenic role of NDRG1 extends beyond classical mechanisms. In glioblastoma, elevated NDRG1 expression is associated with increased microvessel density and vasculogenic mimicry, implicating its involvement in both endothelial-dependent and -independent neovascularization [34–36]. In vivo, NDRG1 knockdown significantly attenuates pulmonary vascular remodeling and right ventricular hypertrophy in rodent models of hypoxia-induced pulmonary hypertension [10, 37], further establishing its role not only as a hypoxia-inducible marker but also as an active driver of endothelial dysfunction and disease progression.

Collectively, available evidence identifies NDRG1 as a hypoxia-inducible effector in ECs, linking HIF-1α–dependent transcription to mitochondrial remodeling, glycolytic adaptation and angiogenic activation. In acute hypoxia, these functions may preserve endothelial viability and barrier function, whereas in chronic hypoxia, sustained NDRG1 activity contributes to pathological vascular remodeling, as demonstrated in models of pulmonary hypertension and ischemia.

Despite these advances, most mechanistic insight is extrapolated from cancer or non-endothelial systems, and direct in vivo studies in vascular beds remain limited. The extent to which NDRG1’s metabolic and mitochondrial effects in ECs are protective versus maladaptive likely depends on oxygen dynamics, upstream co-regulators (e.g., KLF4, TAF15), and vascular bed–specific contexts, but these determinants remain incompletely defined. Systematic evaluation of NDRG1 modulation across acute and chronic hypoxia models, including endothelial-specific loss- and gain-of-function approaches, is needed to clarify its role as either a vascular protector or driver of hypoxia-induced pathology.

NDRG1 and the thromboinflammatory switch in endothelial cells

Vascular Inflammation is a key driver of endothelial dysfunction, triggering the transition of ECs from a quiescent to a proadhesive and prothrombotic state that initiates a cascade of events leading to development and progression of vascular injury [38]. In response to proinflammatory cytokines such as TNF-α and IL-1β, activated ECs upregulate adhesion molecules (e.g., VCAM-1, ICAM-1, E-selectin), secrete inflammatory mediators (e.g., MCP-1, IL-8) and promote leukocyte adhesion and uncontrolled trans-endothelial migration into the subendothelial space, early steps in the development of atherosclerosis and other inflammatory vascular diseases. Prolonged inflammatory signaling further amplifies EC-derived cytokine release, reinforcing endothelial-leukocyte crosstalk and sustaining the inflammatory response. This persistent activation compromises junctional integrity, promotes vascular leakage and accelerates plaque formation, destabilization and ultimately, cardiovascular events such as myocardial infarction, peripheral artery disease and stroke [38, 39].

Recent evidence demonstrates that NDRG1 expression is robustly upregulated in ECs upon stimulation by proinflammatory cytokines such as IL-1β and TNF-α, both in vitro and in human and murine atherosclerotic lesions [9]. This induction is time- and dose-dependent, reinforcing NDRG1’s relevance as a transcriptional target in inflammatory vascular environments. Functional studies in HUVECs (human umbilical vein endothelial cells) show that NDRG1 is required for the full proinflammatory response: its knockdown reduces the expression of inflammatory mediators (IL-6, IL-8, and MCP-1) and downregulates surface presentation of VCAM-1 and ICAM-1, critical components of leukocyte recruitment. Consequently, monocyte adhesion and transendothelial migration are attenuated, indicating that NDRG1 is essential for establishing the adhesive and chemotactic landscape of inflamed endothelium [9].

Beyond immune cell recruitment, NDRG1 plays a central role in promoting the endothelial procoagulant phenotype. Under basal and inflammatory conditions, NDRG1 shortens clotting times by promoting the transcription of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF), key factors involved in thrombin generation, fibrin stabilization and platelet adhesion. Concurrently, NDRG1 suppresses the expression of antithrombotic regulators including thrombomodulin (TM) and tissue-type plasminogen activator (t-PA) [9]. In vivo studies using endothelial-specific NDRG1 knockout mice also demonstrated that the deletion of NDRG1 significantly protected against arterial thrombus formation after injury, highlighting its contribution to the thromboinflammatory phenotype.

Mechanistically, NDRG1 facilitates thromboinflammatory signaling in ECs by interacting with the nuclear receptor Nur77, a known suppressor of vascular inflammation [9, 40]. NDRG1 binds to the DNA-binding domain of Nur77, inhibiting its transcriptional activity and thereby relieving repression of the NF-κB and AP-1 pathways, two major transcriptional axes that drive the expression of cytokines, adhesion and procoagulant molecules [9]. In parallel, endothelial inflammation triggered by excessive levels of the glycolytic byproduct methylglyoxal (MG) has been shown to activate SGK1, which phosphorylates NDRG1 and enhances NF-κB signaling, leading to increased leukocyte recruitment and microvascular permeability [41].

In addition to ECs, NDRG1 also contributes to inflammatory signaling within other vascular compartments. In pulmonary artery smooth muscle cells (PASMCs), NDRG1 overexpression upregulates proinflammatory cytokines such as IL-6 and TNF-α and enhances cell proliferation, eventually contributing to arterial wall thickening. Moreover, PASMCs overexpressing NDRG1 promote the activation, proliferation and migration of cocultured fibroblasts, further elevating TNF-α expression and smooth muscle actin (SMA) levels [42]. These findings suggest that NDRG1 mediates paracrine inflammatory crosstalk within the vascular wall, potentially contributing to maladaptive remodeling.

However, beyond the vascular endothelium, the role of NDRG1 in inflammation appears more variable. In endometrial and prostate epithelial cells, NDRG1 suppresses inflammation by downregulating NF-κB or JNK signaling [43, 44]. In contrast, in gastric cancer cells, NDRG1 activates a JNK/AP-1-dependent mechanism that induces IL-1α and CXC chemokines [45], with nuclear localization correlating with macrophage infiltration and angiogenesis [46]. Conversely, in airway epithelial cells, NDRG1 supports barrier integrity and reduces permeability [47]. These divergent outcomes likely reflect differences in upstream kinase engagement (e.g., SGK1 vs. JNK), subcellular localization (e.g., nuclear vs. cytoplasmic NDRG1) and cell-type-specific transcriptional cofactors.

Collectively, these findings frame NDRG1 as a molecular rheostat of inflammation, capable of amplifying, suppressing, or redirecting responses depending on local metabolic, mechanical, and transcriptional cues. In ECs, current evidence supports a predominantly proinflammatory, prothrombotic role, driven by Nur77 inhibition and NF-κB/AP-1 activation, that is consistent across cytokine and glycolytic stress stimuli and extends to paracrine activation of other vascular wall cells (Fig. 3). However, most mechanistic data derive from isolated cell systems, and only a few endothelial-specific knockout studies directly link NDRG1 to chronic vascular disease. The context-dependent anti-inflammatory roles observed in non-vascular tissues underscore the need for systematic in vivo studies across distinct vascular beds and disease models to define when NDRG1 functions as a driver of pathology versus a mediator of adaptive homeostasis.

Fig. 3.

NDRG1 integrates inflammatory, thrombotic and remodeling pathways in the vascular wall. (A) In endothelial cells, NDRG1 is upregulated by pro-inflammatory cytokines (e.g., IL-1β, TNF-α), promoting the expression of IL-6, IL-8, MCP-1, and adhesion molecules (VCAM-1, ICAM-1), which facilitate leukocyte recruitment and sustain the inflammatory response. B NDRG1 promotes a pro-thrombotic endothelial phenotype by inducing the transcription of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor (vWF), while repressing thrombomodulin and tissue-type plasminogen activator (tPA). Mechanistically, NDRG1 binds the DNA-binding domain of Nur77, inhibiting its anti-inflammatory activity and relieving repression of NF-κB and AP-1–dependent genes. Under inflammatory conditions, serum/glucocorticoid regulated kinase 1 (SGK1)-mediated phosphorylation of NDRG1 amplifies NF-κB signaling. (C) In vascular smooth muscle cells, NDRG1 overexpression increases IL-6 and TNF-α production and promotes cell proliferation. These effects extend to neighboring fibroblasts, enhancing their activation, proliferation, and migration, thereby contributing to vascular remodeling

NDRG1 and the flow-induced reprogramming of endothelial cells

In the dynamic vascular environment, shear stress, defined as the tangential frictional force of blood flow on the endothelial surface, is a key modulator of EC function. While uniform, unidirectional laminar shear stress (LSS) in straight arteries promotes EC quiescence and vascular homeostasis, oscillatory shear stress (OSS) in regions of disturbed flow triggers endothelial dysfunction and reprogramming [48]. OSS increases ROS, induces oxidative stress, disrupts junctional integrity and drives ECs toward pro-inflammatory and mesenchymal-like phenotypes. This transformation, termed flow-induced reprogramming of endothelium (FIRE), includes endothelial-to-mesenchymal transition (EndMT) and immune-like transition (EndIT), contributing to neointimal thickening, immune cell infiltration and plaque progression [48].

Among these mechanoadaptive responses, NDRG1 has emerged as a flow-sensitive gene upregulated under disturbed flow conditions [49, 50]. While traditionally associated with laminar flow and induced growth suppression [51], recent transcriptomic analyses and single-cell sequencing have identified NDRG1 as upregulated in ECs exposed to low, oscillatory shear stress, particularly in atheroprone regions [52–54]. This context-specific upregulation contrasts its role in LSS, suggesting that NDRG1 may participate in distinct shear-dependent signaling programs, shaped by the mechanical microenvironment (Fig. 4).

Fig. 4.

NDRG1 integrates oscillatory shear stress with endothelial reprogramming and dysfunction. (A) Straight-flowing arteries are exposed to unidirectional and homogeneous laminar shear stress (LSS), the intensity of which, low or high, depends on the vascular diameter. Areas of bifurcation or curvature exhibit disturbed flow, generating oscillatory shear stress (OSS). (B) OSS induces endothelial dysfunction characterized by increased production of reactive oxygen species (ROS), oxidative stress, and impaired tight junction integrity. This functional reprogramming, referred to as Flow-Induced Reprogramming of the Endothelium (FIRE), leads to two major phenotypic transitions: the endothelial-mesenchymal transition (EndMT) and the endothelial immune-type transition (EndIT). (C) Exposure to OSS increases NDRG1 expression in endothelial cells, correlated with regulation of the junctional protein claudin-9. PIM1 kinase phosphorylates NDRG1 at serine 330, promoting its nuclear translocation. In the nucleus, NDRG1 interacts with polypyrimidine tract-binding protein 1 (PTBP1), which potentiates EndMT in response to oxidized low-density lipoprotein (oxLDL) exposure

Although the precise function of NDRG1 in disturbed flow remains to be fully elucidated, emerging evidence suggests a role in both endothelial barrier disruption and mesenchymal reprogramming. Proteomic analyses have linked OSS with altered NDRG1 expression and concurrent changes in junctional components such as claudin-9, pointing to a potential role in modulating endothelial integrity [47]. Further mechanistic insights come from atherosclerosis models, where the serine/threonine kinase PIM1, upregulated during disease progression, drives EndMT and endothelial migration through phosphorylation of NDRG1 at serine 330 [55]. Endothelial-specific knockdown of PIM1 reduces NDRG1 phosphorylation and nuclear translocation, weakening its interaction with the RNA-binding protein PTBP1. This disruption attenuates the expression of mesenchymal markers including Vimentin, Slug, Snail and α-SMA, thereby limiting the phenotypic transition induced by oxLDL exposure [55].

Together, current findings identify NDRG1 as a mechanosensitive integrator of hemodynamic cues, translating disturbed flow into endothelial reprogramming and phenotypic drift. Its expression is suppressed under steady laminar shear but induced by oscillatory shear in atheroprone regions, where it has been linked to EndMT, mesenchymal marker expression, and junctional destabilization via upstream effectors such as PIM1 and partners like PTBP1. These data suggest a predominantly maladaptive role in disturbed flow, potentially driving atherogenesis.

Yet, this view remains provisional. Most functional evidence derives from oxLDL or inflammatory co-stimulation models rather than pure mechanical perturbation, and whether NDRG1’s effects vary by vascular bed, phosphorylation state, or binding partners is unknown. Protective roles under physiological laminar shear are also largely untested beyond early transcriptomic observations. Defining the context-specific functions of NDRG1 will require endothelial-specific manipulation in well-characterized flow models across distinct vascular territories to determine whether it acts as a driver of pathology, an adaptive responder, or both.

NDRG1 and the redox-metabolic response to heavy metal exposure

While trace levels of heavy metals are essential for vascular function, chronic exposure or systemic accumulation, often linked to industrialization and environmental contamination, induces oxidative stress, mitochondrial dysfunction and transcriptional dysregulation, compromising endothelial homeostasis and promoting CVDs [56, 57]. NDRG1 has emerged as a versatile metal-binding protein, with a histidine-rich C-terminal repeat domain that confers high-affinity binding to divalent cations such as Ni²⁺, Cu²⁺, and Co²⁺ [58]. This positions NDRG1 at the interface of redox regulation, metal detoxification, and cellular adaptation.

IRON (Fe)

Iron is indispensable for oxidative phosphorylation and vascular homeostasis, yet both iron overload and deficiency are associated with endothelial dysfunction and increased CVD risk. Excess free iron catalyzes hydroxyl radical production via Fenton chemistry, damaging lipids, proteins and DNA, while iron deficiency impairs mitochondrial respiration and ATP production [59–61]. Clinical studies link low serum iron levels to increased atherosclerosis risk, underscoring iron's complex vascular role [62].

NDRG1 is a classical iron-responsive gene, strongly induced under conditions of iron depletion, including treatment with desferrioxamine (DFO) or Dp44mT [63, 64]. This response is mediated through both HIF-1α-dependent mechanisms, where iron deprivation stabilizes hypoxia-inducible factor and activates HREs in the NDRG1 promoter, and HIF-1α-independent pathways involving transcription factors like Egr-1, Sp1, and stress granule-associated eIF3a [63, 65, 66].Paradoxically, while low iron induces NDRG1, the protein itself acts as a stabilizer of intracellular iron metabolism, particularly under fluctuating or pathological conditions. Studies in cardiomyocytes and hepatocytes show that NDRG1 contributes to iron homeostasis by regulating transferrin receptor recycling and buffering iron overload, thereby limiting lipid peroxidation and susceptibility to ferroptosis [67, 68]). While these functions remain to be confirmed in ECs, they point to a potential cytoprotective role for NDRG1 in iron-induced vascular stress (Fig. 5).

Fig. 5.

Iron imbalance, endothelial dysfunction and NDRG1-mediated adaptive responses. (A) Iron overload catalyzes the formation of hydroxyl radicals via the Fenton reaction, leading to DNA damage, lipid peroxidation, and protein oxidation. These alterations lead to mitochondrial dysfunction, reduced nitric oxide (NO) bioavailability, and endothelial inflammation. (B) Conversely, iron deficiency compromises mitochondrial respiration and decreases ATP production. Iron depletion induced by desferrioxamine (DFO) or di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) increases NDRG1 expression in endothelial cells through a HIF-1α-dependent mechanism, involving its binding to the hypoxia response element (HRE) of the NDRG1 promoter. HIF-1α-independent pathways, involving factors such as Egr-1, Sp1, and stress granules-associated aIF3a, also contribute to the increase in NDRG1. (C) NDRG1 modulates transferrin (Tf) metabolism. Its deregulation disrupts intracellular iron homeostasis, promoting iron accumulation, lipid peroxidation, and ferroptosis

Nickel (Ni²⁺), Copper (Cu²⁺) and Cobalt (Co²⁺): Shared Mechanism of NDRG1 Modulation

Nickel, copper and cobalt share key pathophysiological features as redox-active metals that induce endothelial dysfunction through oxidative stress, impaired NO signaling and pro-inflammatory transcriptional activation.

• (i)Nickel, impairs NO bioavailability by disrupting endothelial nitric oxide synthase (eNOS) activity [69] and induces inflammation in vascular beds [70, 71]. It triggers NDRG1 expression via intracellular Ca²⁺ elevation and may mimic hypoxia to activate the HIF pathway [72–74]. These observations support a model in which NDRG1 contributes to nickel-induced redox adaptation.
• (ii)Copper, while essential, becomes deleterious at high levels. It potentiates oxidative stress by interacting with homocysteine and promoting mitochondrial damage, apoptosis and vascular remodeling [35, 75]. The detection of elevated copper levels in human serum and atherosclerotic plaques and their correlation with carotid intima-media thickness, support the notion that disrupted copper handling contributes to increased risk of CVD [35, 76, 77]. Although copper does not strongly induce NDRG1 transcription, the protein’s ability to bind Cu²⁺ suggests a buffering or detoxifying role [78]. Its early identification as a gene upregulated in endothelial cells exposed to redox stress supports its relevance in copper toxicity [79].
• (iii)Cobalt chronic exposure has also been associated with direct generation of ROS, a recognized driver of endothelial dysfunction and atherosclerosis [80–82]. Cobalt stabilizes HIF-1α and activates pro-inflammatory pathways such as NF-κB, mimicking hypoxia and increasing VEGF and NDRG1 expression [71, 83–85]. Cobalt exposure has been linked to atherosclerosis and vascular inflammation, raising the possibility that NDRG1 participates in hypoxia-like transcriptional programs and cellular adaptation.

Across metals, NDRG1 induction converges on shared signaling hubs, HIF-1α, NF-κB, and mitochondrial homeostasis, yet causal data in endothelial models are scarce. Most mechanistic insights derive from cancer cells or peptide biochemistry, with limited validation in intact vascular systems. Whether NDRG1’s metal-responsive induction serves a detoxifying, cytoprotective role or contributes to maladaptation likely depends on metal species, exposure duration, and vascular bed. Rigorous in vivo studies will be required to define its position in the endothelial defense-injury balance under metal stress.

Conclusions and outstanding questions

This review positions NDRG1 as a dynamic mediator of endothelial adaptation, responding to a wide spectrum of environmental, mechanical and metabolic stressors that are central to cardiovascular homeostasis and pathology. Beyond its well-characterized roles in cancer and systemic stress responses, NDRG1 is emerging as a context-sensitive effector in the vascular endothelium. It interprets cues from hypoxia, inflammation, disturbed shear stress and redox-active metal exposure to modulate endothelial phenotype, permeability, inflammatory tone and remodeling capacity. These findings place NDRG1 not merely as a downstream responder but potentially as a hub in the orchestration of vascular stress programs (Table 1).

Table 1.

Summary of NDRG1 Effects Under Distinct Vascular Stress Conditions: Direct Endothelial Cell Evidence and Mechanistically Relevant Findings from Related Cell Types

Stress Type		NDRG1 Effect	Model/Study Type	Key Mechanistic	Outcome	References
Hypoxia		Protective (acute hypoxia) vs Maladaptive (chronic hypoxia)	Human pulmonary artery EC; hypoxia-induced pulmonary hypertension rat model	NDRG1 binds TAF15 → promotes nuclear localization → activates PI3K–Akt, p53, and HIF-1 pathways	Enhances EC dysfunction, migration, and angiogenesis	[10]
			Human pulmonary artery smooth muscle cells (PASMC) (in vitro) and rat hypoxia model (in vivo)	NDRG1 → DRP1, PI3K/Akt/mTOR activation; upstream regulator KLF4	Promotes PASMC proliferation, migration, and survival under hypoxia	[16]
			JEG-3 placental-derived cells (in vitro)	NDRG1 binds PI3K; knockdown ↑ PI3K/AKT signaling, ↑ VEGF & PLGF, ↓ sFlt-1	Overexpression limits angiogenesis; knockdown enhances pro-angiogenic signaling	[30]
Inflammation		Maladaptive	Human & mouse ECs in vitro; human & murine atherosclerotic lesions; EC-specific NDRG1 KO mice	Cytokine stimulation ↑ NDRG1 → interacts with Nur77 → inhibits Nur77 & enhances NF-κB/AP-1 activity → ↑ cytokines, adhesion molecules, TF, PAI-1; ↓ TM, t-PA	Promotes endothelial activation, thrombosis, and remodeling	Yu et al., 2009; [9]
			Ndrg1 KO mice; bone marrow–derived macrophages; tumor and corneal angiogenesis model	NDRG1 promotes differentiation of macrophage lineage cells (osteoclasts, M1/M2 macrophages, dendritic cells); ↑ tumor-associated macrophage infiltration	NDRG1 deficiency reduces inflammatory angiogenesis and tumor growth	[32]
			Intravital microscopy in mouse cremaster	MethylglyoxalInflammation → activates SGK1 → phosphorylates NDRG1 (Thr346/356/366) → activates NF-κB and CREB → ↑ adhesion molecules (P-/E-selectin, ICAM-1) → ↑ leukocyte recruitment and microvascular permeability	Promotes endothelial inflammation and barrier dysfunction	Su et al., 2024
			PASMCs and cocultured fibroblasts; overexpression/knockdown	NDRG1 ↑ → PASMC IL-6, TNF-α ↑ → fibroblast TNF-α & SMA ↑; ↑ fibroblast proliferation & migration	Amplifies vascular wall inflammation and fibroblast activation, potentially contributing to vascular remodeling	Huang & Zhang, 2024
			Primary ECs (ox-LDL stimulation) and ApoE-/- mice with EC-specific PIM1 knockdown	Ox-LDL → ↑ PIM1 → phosphorylates NDRG1 at Ser330 → NDRG1 nuclear translocation → binds PTBP1 → ↑ mesenchymal gene expression (Vimentin, ZEB1, Slug, Snail, N-Cadherin, TAGLN, α-SMA)	Drives EndMT, increases plaque size, lipid content, and destabilization markers	[55]
Shear stress		Protective (Pulsatile shear) vs Maladaptive (Oscillatory shear)	ECs (in vitro flow chamber & in vivo arteries)	Transcriptional induction as part of flow-adaptive gene program	Flow-responsive gene, potential role in endothelial adaptation	[51]
			Human ECs, SILAC-based proteomics	Not mechanistically examined; study focus on basement membrane remodeling (LAMA4/LAMA5, integrins)	EC adaptation to shear and extracellular matrix remodeling	[52]
			Human aortic ECs, single-cell RNA-seq	Not mechanistically examined; study focuses on flow-dominant transcriptional adaptation	Flow alters EC transcriptome and modulates drug response capacity	[54]
			Human aortic ECs, RNA-seq	Comparative transcriptional dynamics between EC types under shear stress	Flow alters EC transcriptome with cell-type–specific kinetics	[53]
Heavy Metal Exposure	Iron Depletion	Protective	Cancer models with vascular readouts (VEGF/angiogenesis)	Iron chelators (DFO, Dp44mT) ↑ NDRG1; ↑ Thtpa, ↓ cathepsin C; ↓ VEGF	Reduces pathological angiogenesis and invasion (tumor context); consistent with vascular protection	[63],[64]
	Iron overload	Maladaptative	Human brain microvascular ECs in vitro; mouse brain microvasculature in vivo	Iron exposure ↑ NDRG1; oxidative stress, cytoskeletal changes, tight-junction disruption	Endothelial barrier failure/BBB leak → vascular injury	[66]
	Nickel	Indeterminate (marker of stress; exposure itself is maladaptive)	Synthetic NDRG1 C-terminal peptides (NMR)	Each His-containing repeat binds 1–3 Ni2+ ions (pH-dependent coordination geometry); Ni2+ binding organizes local side chain conformation	Identifies NDRG1 as a direct Ni2+-binding protein with potential conformational regulation relevant to vascular stress	[78]
			Human ECs	Ni2+ induction via increased intracellular Ca2+; mimicked by Ca2+ ionophores; blocked by Ca2+ chelation; independent of oxidative stress	Suggests NDRG1 as a Ca2+-responsive stress protein with potential vascular relevance in nickel toxicity	[72]
	Copper	Indeterminate	HUVECs and other cell lines	Induces NDRG1 (Cap43) via metal-responsive elements, independent of HIF-1	Points to NDRG1 as a copper-stress sensor; impact on EC function not defined	[78]
	Cobalt	Context-dependent/likely maladaptive	ECs/various cells (literature consensus)	Co2+ stabilizes HIF-1α → ↑ NDRG1/VEGF/NF-κB signaling	Hypoxia-mimetic response can drive angiogenesis/inflammation; EC outcomes need direct testing	[85]

Yet, despite expanding mechanistic insight, critical questions remain. One of the most pressing gaps lies in understanding the temporal and spatial specificity of NDRG1 signaling within vascular beds. While the current literature focuses on systemic vasculature, the cerebral endothelium, which is a highly specialized and tightly regulated barrier with unique metabolic and immune profiles, remains virtually unexplored in this context. Given the susceptibility of brain endothelial cells to oxidative injury, metabolic stress and inflammatory cascades during cerebrovascular insults such as ischemic stroke, it is tempting to hypothesize that NDRG1 might participate in neurovascular adaptation or maladaptation. Its known regulation by hypoxia and redox signals, combined with its roles in mitochondrial dynamics and ferroptosis resistance, invites speculation that NDRG1 could influence endothelial fate decisions within the brain, particularly under conditions of reperfusion injury, metabolic collapse, or blood–brain barrier compromise.

Further investigation is needed to determine whether NDRG1 expression or activity differs between peripheral and cerebral endothelial populations, and whether its modulation might confer protection or, conversely, exacerbate damage in stroke models. Such studies would benefit from refined spatial and temporal tools, including single-cell profiling, inducible endothelial-specific models, and high-resolution mapping of NDRG1 post-translational modifications. The intersection between NDRG1 and emerging cell death modalities such as ferroptosis and cuproptosis also remains insufficiently defined, particularly in the context of vascular inflammation and metal-induced endothelial injury.

From a translational standpoint, the druggability of NDRG1 remains uncertain. As a non-enzymatic scaffold protein lacking intrinsic catalytic activity, it is not readily amenable to conventional small-molecule inhibition. Its broad tissue distribution and context-dependent functions further complicate systemic targeting. Feasible strategies may instead involve modulating upstream regulators (e.g., HIF-1α, PIM1, SGK1), altering post-translational modifications, or disrupting specific protein–protein interactions (such as with Nur77 in endothelial inflammation or PTBP1 in disturbed flow). Experimental approaches including proteolysis-targeting chimeras (PROTACs), peptide mimetics, or targeted delivery systems (e.g., nanoparticle-based siRNA) could offer more selective modulation, but each carries technical and safety challenges that must be addressed in vascular models before clinical consideration.

While in vitro endothelial systems and some endothelial-specific knockout models have provided valuable mechanistic insights, the functional role of NDRG1 across the spectrum of cardiovascular diseases remains far less explored in vivo. Genetic mouse models, particularly those allowing temporal and vascular bed–specific manipulation, are rarely employed in contexts such as atherosclerosis, ischemia–reperfusion injury, heart failure, or cerebrovascular disease. Leveraging such models would be instrumental in defining causal links between NDRG1 activity and disease progression, capturing the spatial and temporal specificity of its actions, and determining whether modulating NDRG1 can enhance endothelial resilience without compromising homeostatic functions. Addressing these gaps is essential for translating cell-based findings into clinically meaningful interventions.

As research continues to uncover the layered complexity of endothelial biology, NDRG1 may prove to be a previously underappreciated integrator at the crossroads of vascular health and disease. Its potential relevance to the cerebral endothelium, and thus to neurovascular disorders like stroke, underscores the urgency of expanding this field beyond the systemic vasculature. Defining the boundaries and possibilities of the endothelial NDRG1 axis through rigorous in vivo modeling may ultimately open new therapeutic frontiers in cardiovascular and cerebrovascular medicine.

Authors' contributions

FD conceived the review. FD and TE wrote the manuscript and designed the figures. DV & YR critically revised the text and approved the final version.

Funding

The authors reported there is no funding associated with the work featured in this review.

Data availability

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Declarations

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Conflict of interest

The authors declare no conflict of interest.

Competing interests

The authors declare that they have no competing interests.