Poly(ADP-ribose) polymerase (PARP) inhibitors in cardiovascular, and cerebrovascular diseases: mechanisms, current trends and challenge for clinical translation

Energy depletion and metabolic collapse

PARP1 hyperactivation consumes vast quantities of cellular NAD⁺, a critical coenzyme for energy metabolism. The catastrophic depletion of the NAD⁺ pool cripple glycolysis and oxidative phosphorylation, leading to a severe drop in ATP levels. This energy crisis impairs essential cellular functions, particularly in high-energy-demand cells like cardiomyocytes and neurons, ultimately driving them towards programmed cell death.

In hypertension or heart failure, mitochondria also serve as primary sources of endogenous ROS generation (Ordog et al., 2021). When the antioxidant defense system becomes insufficient, endogenous reactive oxygen species (ROS) accumulate and damage key cellular structures, including nuclear and mitochondrial DNA (Kowaltowski et al., 2009). ROS directly oxidize nucleobases (Shokolenko et al., 2009; Srinivas et al., 2019), thereby activating PARP1 and triggering severe depletion of mitochondrial NAD⁺ levels, which exacerbates oxidative protein and DNA damage. Endothelial dysfunction in diabetes, hypertension, atherosclerosis, shock, and heart failure is mechanistically linked to localized overproduction of reactive oxygen/nitrogen species and PARP activation within vascular endothelial cells. Myocardial or endothelial cells with DNA damage can enter three primary pathways depending on the severity of DNA lesions and the extent of PARP activation (Pacher & Szabó, 2007). Under mild-to-moderate DNA damage, such as occurs in cardiomyocytes or endothelial cells during transient ischemia, PARP1 activation recruits DNA repair enzymes to correct lesions, promoting cellular survival. Moderate PARP activation reduces cellular NAD⁺ levels without causing lethality; such energy-compromised cells exhibit reversible dysfunction, and PARPi can partially restore energy metabolism to rescue cells from this dysfunctional state (Graziani & Szabó, 2005; Pacher & Szabó, 2007; Virág et al., 2013). The third pathway, triggered by extensive DNA damage, involves PARP hyperactivation leading to catastrophic NAD⁺ depletion and mitochondrial collapse. In this pathway, PARPi show limited efficacy by partially attenuating mitochondrial dysfunction, ROS release, and mitochondrial death factor liberation (Hong, Dawson & Dawson, 2004; Wang, Dawson & Dawson, 2009). Activation of the DNA damage-PARP1-NAD⁺ axis compromises genomic integrity, disrupts mitochondrial homeostasis, and ultimately culminates in cardiomyocyte dysfunction (Hassa & Hottiger, 2008). This exacerbates ROS production, elevates intracellular Ca²⁺, disrupts mitochondrial membrane integrity via permeability transition, and ultimately induces necrosis in cardiomyocytes and endothelial cells due to impaired glycolysis, Krebs cycle dysfunction, and mitochondrial electron transport chain failure (Dawson & Dawson, 2004; Halmosi et al., 2001; Song et al., 2013; Virág & Szabó, 2002; Wang, Dawson & Dawson, 2009; Yu et al., 2006). This axis also operates in coronary artery disease, where hypoxia-reoxygenation cycles exacerbate oxidative stress and free radical release, promoting DNA damage, PARP activation via PARylation stimulation, and consequent NAD⁺/ATP depletion (Ramos & Brundel, 2020). Furthermore, the DNA damage-PARP1-NAD⁺ axis contributes to hypertension-associated endothelial dysfunction (Carrillo et al., 2005), Lamin A/C gene (LMNA) mutation-induced dilated cardiomyopathy (Diguet et al., 2018), and peripartum cardiomyopathy pathogenesis (Ricke-Hoch, Pfeffer & Hilfiker-Kleiner, 2020).

In summary, PARP1 hyperactivation serves as a central pathogenic hub that links oxidative stress, DNA damage, and metabolic collapse. Cells with high energetic demands—such as cardiomyocytes, endothelial cells, and neurons—are particularly vulnerable to NAD⁺ depletion and the downstream consequences of excessive PARP1 activation. Optimizing PARPi dosing, therapeutic timing, and disease-stage specificity is therefore critical in conditions such as hypertension, diabetes, ischemia–reperfusion injury, and heart failure. While PARPi can restore metabolic homeostasis under moderate DNA damage, their therapeutic efficacy becomes markedly constrained once severe genomic injury, catastrophic NAD⁺/ATP depletion, or mitochondrial permeability transition has occurred. Consequently, combination approaches—such as co-administration of PARPi with NAD⁺ precursors, mitochondrial stabilizers, or ROS scavengers—may offer superior cytoprotective benefits. Furthermore, the development of tissue-targeted delivery systems that preferentially direct PARPi to cardiac or vascular tissues could help minimize systemic metabolic liabilities. Collectively, these strategies hold promise for achieving therapeutic benefit without compromising the essential DNA repair functions of PARP1.

Modulation of cell death pathways

The hyperactivation of PARP1 is a critical driver of cell death. Cellular energy status is a critical determinant of the mode of cell death. The severe ATP depletion caused by PARP1 hyperactivation inhibits the energy-dependent apoptotic program and forces the cell into an uncontrolled, pro-inflammatory necrotic pathway. By preserving NAD⁺ and ATP pools, PARPi can reprogram cell fate, shifting the balance from necrosis towards apoptosis or even promoting cell survival and functional recovery.

Research has demonstrated that pharmacological inhibition of PARP1 shifts cell death modalities to apoptosis (Virág, Salzman & Szabó, 1998). In cells subjected to ROS damage, PARPi prevents necrotic cell death while permitting apoptotic pathways or even restoring normal phenotypic states, thereby reprogramming cell fate from necrosis to apoptosis or phenotypic normalization. Notably, PARPi or genetic ablation provides the most profound protection in disease models dominated by cell death, including stroke, myocardial infarction, and mesenteric ischemia-reperfusion injury (Kim et al., 2018; Virág & Szabó, 2002).

Cell death is also further promoted by the mitochondrial release of apoptosis-inducing factor (AIF) (Wang et al., 2016). Persistent PARP1 activity also suppresses NAD⁺-dependent deacetylase Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), leading to mitochondrial dysfunction. Conversely, PARPi counteract these effects by preserving NAD⁺ levels, which in turn activates the SIRT1-AMPK pathway, restores mitochondrial function, and promotes cell survival (Cheng et al., 2003). They also maintain cellular homeostasis by preventing mitochondria-mediated cell death through the inhibition of AIF release. In the context of hyperglycemia, PARP1 activation directly modulates apoptotic signaling. Pharmacological inhibition of PARP1mitigates high glucose-induced cardiomyocyte apoptosis by downregulating cleaved-Caspases3 and cleaved-Caspases9 and concurrently activating the pro-survival insulin-like growth factor 1 receptor (IGF-1R)/Akt pathway (Qin et al., 2016).

Ferroptosis is a distinct form of regulated cell death driven by the iron-dependent accumulation of lipid peroxides and ROS, distinguishing it from canonical pathways such as apoptosis, necroptosis, and autophagy (Dixon et al., 2012). Recent research has revealed that PARPi can mitigate ferroptosis in cardiomyocytes, vascular smooth muscle cells (VSMC), and leukocytes (Yang et al., 2025a). PARP1-mediated PARylation-dependent ubiquitination of DNA Polymerase gamma (POLG) in VSMC ferroptosis (Yang et al., 2025a). The other research found that the protective effect of PARPi may be mediated by PARP1 ability to promote mitophagy, which preserves mitochondrial integrity and prevents the triggers of ferroptosis (Liu et al., 2024). Collectively, these findings indicate a potent protective role for PARPi in programmed cell death pathways.

Pro-inflammatory signaling

PARP1 functions as a transcriptional regulator that influences inflammatory responses and cell survival through the modulation of nuclear factor-κB (NF-κB), p53, and hypoxia-inducible factor-1α (HIF-1α) (Elser et al., 2008; Hassa et al., 2003; Salameh et al., 2020; Wiman, 2013). Its activation promotes the expression of cytokines, chemokines, and adhesion molecules, fueling a persistent inflammatory state that contributes to endothelial dysfunction, atherosclerotic plaque progression, and adverse tissue remodeling. In the myocardial ischemia-reperfusion injury, PARP1 hyperactivation amplifies NF-κB signaling, which upregulates adhesion molecules like P-selectin and intercellular adhesion molecule-1 (ICAM-1) and enhances leukocyte-endothelial interactions (Song et al., 2013; Zingarelli, Salzman & Szabó, 1998). This cascade promotes neutrophil infiltration into myocardial tissue, thereby exacerbating inflammation and tissue injury. Consistent with this role, treatment with PARPi has been shown to decrease the levels of inflammatory mediators, including tumor necrosis factor-α (TNF-α) leading to the attenuation of myocardial inflammation (Yang, Zingarelli & Szabó, 2000). SIRT1, a member of Sirtuin family, exerts multifaceted endothelial protection by deacetylating substrates that normally suppress NF-κB-mediated gene expression. However, PARP1 inhibits SIRT1 activity in cardiomyocytes, and during severe ischemia, this imbalance accelerates caspase activation and PARP cleavage prior to atherosclerotic plaque rupture and necroptosis (Alhosaini et al., 2021; Kauppinen et al., 2013; Xu et al., 2014; Yeung et al., 2004).

Beyond its canonical role in DNA repair, PARP1 acts as a transcriptional integrator that connects metabolic stress to inflammatory gene expression via regulators such as NF-κB and HIF-1α. In cardiovascular and cerebrovascular contexts, PARP1 coordinates a multifaceted network of metabolic and inflammatory signals. Elucidating its context-specific functions and optimizing targeted intervention strategies will be key to realizing the full translational potential of PARP1 inhibition in clinical medicine.

Ischemic diseases

In ischemic diseases, ischemia-reperfusion (I/R) injury primarily induces cardiomyocyte and neuronal cell death through programmed cell death mechanisms, with apoptosis playing a significant contributory role. I/R-triggered ROS generation causes oxidative DNA strand breaks, thereby activating PARP1. PARP activation disrupts cellular metabolic efficiency by transferring the ADP-ribosyl moiety from NAD⁺ to protein receptors, leading to depletion of ATP and subsequent cell death. This mechanism underlies cardiomyocyte apoptosis and necroptosis following I/R injury (Fiorillo et al., 2006; Lord et al., 2009).

When PARP1 is activated, PARylation triggers histone H1 dissociation from Forkhead box O3 a (FOXO3a)-target gene promoters, promoting FOXO3a nuclear accumulation and enhancing its binding affinity to these promoters, thereby upregulating autophagy-related gene expression. PARP1 mediates FOXO3a PARylation and facilitates its phosphorylation at residues T32, S252, and S314, which induces nuclear export of FOXO3a, suppresses its transcriptional activity and target gene expression, and ultimately drives myocardial hypertrophy (Lu et al., 2016). PARP1 activation further compromises mitochondrial metabolism by dysregulating FOXO3a-dependent autophagy, thereby accelerating cardiomyocyte death. PARP1 silencing or specific pharmacological inhibitors attenuate ischemia-induced FOXO3a hyperactivity, suppressing cardiomyocyte apoptosis, fibrotic remodeling, and pathological cardiac hypertrophy (Wang et al., 2018a).

PARP inhibition therapy mitigates mitochondrial ROS production and cardiac remodeling while restoring mitochondrial oxidative metabolism and left ventricular function (Ba & Garg, 2011). Pharmacological PARP inhibition also exerts cardioprotective effects across various cardiovascular injuries and heart failure-related cardiac/endothelial dysfunction by reducing plasma biomarkers of cardiomyocyte necrosis and downregulating inflammatory responses. Preserving cellular energy stores constitutes a key mechanism through which PARP inhibition protects against reperfusion injury, thereby improving myocardial functional recovery following cardiac arrest (Kaplan et al., 2005; Yamazaki et al., 2013). In cellular experiments, studies demonstrate that oxidative stress triggers apoptosis signal-regulating kinase 1 (ASK-1)-dependent activation of c-Jun N-terminal kinase (JNK), whereas PARP1 inhibition suppresses JNK activation (Bartha et al., 2009; Mester et al., 2009). Racz et al. (2010) confirmed that H₂O₂ treatment significantly increases p38 and JNK1/2 phosphorylation, while PJ-34—a pharmacological PARP inhibitor—reduces H₂O₂-induced p38 elevation and inhibits JNK activation below baseline levels in WRL-68 cells. Under basal conditions without H₂O₂, PJ-34 does not affect p38 but nearly abolishes JNK activation. Furthermore, PJ-34 treatment enhances cell viability following I/R injury, significantly reducing apoptosis while shifting cell death mechanisms from caspase-independent to caspase-dependent pathways. PARP1 inhibition attenuates oxidative stress-induced mitochondrial membrane potential collapse and secondary ROS generation (Du et al., 2003). In PJ-34-treated cardiomyocytes subjected to ischemia-reperfusion, oxidative stress and PARP1 activity decrease, NAD⁺/ATP depletion attenuates, and mitochondrial damage lessens. PJ-34 treatment not only enhances ischemic cell viability but also reduces apoptosis (Singh & Kang, 2011). Under TGF-β1 stimulation, both PARP1 expression and autophagy increase in cardiac fibroblasts (CFs). PARP1 inhibition partially blocks TGF-β1-induced CF activation by downregulating autophagy, thereby attenuating post-myocardial infarction fibrosis and improving cardiac function. PARP1 inhibition with 4-Aminobenzoic Acid Derivative (4-AB) alleviates myocardial fibrosis and autophagy in infarcted rats (Wang et al., 2018b), while another PARPi 4-Amino-1,8-naphthalimide (4-AN) significantly diminishes AIF-induced apoptosis and improves cardiac function (Singh & Kang, 2011).

Specificity protein 1 (SP1) may exert critical transcriptional regulation in myocardial infarction (MI), where PARP inhibition significantly reduces SP1 expression, ablates its positive regulatory effect on BCL2/adenovirus E1B 19 kDa-interacting protein 3-like (BNIP3L, also name as NIX) transcription, and concurrently suppresses cardiomyocyte viability (Geng et al., 2021). Research reveals that the phosphoinositide 3-kinase (PI3K)/Akt pathway modulates PARPi efficacy: PI3K blockade diminishes PARP inhibitor-mediated phosphorylation of Akt and GSK-3β during ischemia-reperfusion, substantially impairs recovery of ATP and creatine phosphate levels, and attenuates the protective effects of PARPi on infarct size reduction and cardiac functional recovery. This challenges the initial paradigm that NAD⁺ preservation and resultant ATP pool restoration constitute the exclusive mechanism underlying PARPi-mediated cyto-protection, demonstrating that PI3-kinase/Akt pathway activation and its downstream processes contribute equally, if not more substantially, to the cardio-protection afforded by PARPi during reperfusion injury (Kovacs et al., 2006).

In stroke and neurodegenerative diseases, Amelparib (JPI-289, a novel of PARPi) was found can reduce the infarct volume and brain swelling (Kim et al., 2018), by up-regulating regulatory T cells (Tregs) (Noh et al., 2018). For acute, life-threatening conditions such as stroke, myocardial infarction, circulatory shock, PARPi may interfere with NAD⁺-dependent enzymatic processes beyond PARP1. However, this off-target effect may clinically acceptable given the limited therapeutic alternatives and marginal efficacy of existing treatments for these critical diseases. Collectively, these findings indicate that selective pharmacological modulation of PARP1 represents a promising therapeutic strategy for mitigating ischemia-reperfusion injury.

PARP1 exerts dual and context-dependent functions in ischemia–reperfusion injury. While excessive activation promotes energy collapse, inflammation, and cell death, basal PARP1 activity can support adaptive signaling through FOXO3a, autophagy, and pro-survival pathways during myocardial remodeling. This mechanistic duality underscores the need to carefully delineate therapeutic timing and context for PARP inhibition, ensuring efficacy in acute ischemic events without perturbing essential metabolic or immune functions.

Cardiomyopathy and myocardial hypertrophy

PARP inhibition exerts no direct antihypertensive effect but mitigates hypertension-induced myocardial remodeling. Chronic PARP suppression induces persistent beneficial alterations in oxidative stress-associated signaling pathways (Bartha et al., 2009), conferring significant protection against the transition from hypertensive heart disease to heart failure (Bartha et al., 2009; Magyar et al., 2014). PARPi additionally modulate multiple signal transduction cascades: they activate pro-survival pathways (PI3K/Akt-1/GSK-3β, PKCε) that preserve mitochondrial integrity and enhance cellular viability during oxidative stress (Deres et al., 2014; Miyamoto, Murphy & Brown, 2009), while simultaneously suppressing the mitogen-activated protein kinase (MAPK) pathway, including c-Jun N-terminal kinase (JNK) and p38 MAPK, via MKP-1 upregulation (Deres et al., 2014; Jin et al., 2018; Racz et al., 2010). However, reduced MCP-1 expression may paradoxically increase JNK phosphorylation, activating mitochondrial fission and autophagy to impair energy production. PARP inhibition enhances activation of cytoprotective kinases protein kinase B (Akt) and protein kinase Cε (PKCε), while reducing activity of maladaptive remodeling kinases PKCα/β, PKCζ/λ, and PKCδ (Bartha et al., 2008). Through these mechanisms, PARPi attenuate cardiac interstitial fibrosis, left ventricular hypertrophy, and heart failure progression.

Studies have revealed that mitochondrial translocation of PARP1/PAR adversely affects POLG replisome-mediated mitochondrial DNA (mtDNA) maintenance, exacerbating mitochondrial dysfunction, oxidative stress, and cardiac remodeling in Chagas disease. PARP1 inhibitor therapy demonstrates therapeutic potential to preserve mitochondrial health and left ventricular function in chronic cardiomyopathy induced by myocardial ischemia and other etiologies (Ba & Garg, 2011). NAD⁺-dependent histone deacetylase Sirtuin 6 (SIRT6) inactivation during angiotensin II (AngII)-induced cardiac hypertrophy can be counteracted by PARP inhibition-mediated NAD⁺ replenishment, which reverses AngII-driven SIRT6 suppression. Restored SIRT6 activity attenuates myocardial hypertrophy via NF-κB signaling inhibition (Liu et al., 2014b).

In diabetic cardiomyopathy, although PARPi exhibits no significant effect on pre-existing hyperglycemia (Zakaria et al., 2016), PARPi elevates levels of SIRT1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thereby attenuating oxidative stress, inflammation, and fibrotic remodeling (Waldman et al., 2018). PARP1 suppression in diabetic animal models protects cardiomyocytes from inflammatory responses and ROS overproduction (Waldman et al., 2018; Zakaria et al., 2016), while also preserving cardiac function and ameliorating metabolic dysregulation in diabetic hearts (Waldman et al., 2018).

Notably, doxorubicin (Dox)-induced cardiotoxicity—a major limitation in its clinical use—has been closely linked to PARP1 hyperactivation. PARP1 inhibitors effectively attenuate this toxicity, offering a promising strategy to enhance chemotherapeutic safety (Chen et al., 2025; Jiang et al., 2012). Pharmacological PARP inhibition protects cardiomyocytes against both chronic low-grade oxidative stress and acute severe oxidative damage via mitochondrial stabilization, positioning it as a promising therapeutic target for preventing and treating myocardial remodeling and heart failure (Ordog et al., 2021).

In conclusion, PARPi demonstrate substantial cardioprotective potential across multiple forms of cardiomyopathy and pathological myocardial remodeling, acting primarily through the regulation of oxidative stress, and mitochondrial homeostasis to mitigate the progression of hypertensive, ischemic, infectious, and metabolic cardiomyopathies.

Moreover, the central role of PARP1 in mitochondrial integrity, NAD⁺ metabolism, and its interaction with the Sirtuin family underscores the importance of precisely identifying patient populations and optimizing therapeutic timing. Although PARPi consistently confer protection in cardiac injury models such as DOX-induced cardiotoxicity, the multifaceted effects on immune and metabolic pathways present notable challenges for clinical translation. Future research should prioritize defining optimal dosing windows, stratifying interventions by disease stages, and integrating PARPi with complementary strategies, to fully realize the therapeutic potential of PARP-targeted therapies in cardiomyopathy and heart failure.

Atherosclerosis and inflammation

In atherosclerosis and inflammation, 3-aminobenzamide (3-AB), the first PARPi developed for cardiovascular indications—demonstrated a trend toward reducing plasma C-reactive protein and interleukin-6 levels without significantly lowering myocardial injury biomarkers in clinical studies (Pacher & Szabó, 2007, 2008). Mechanistically, PARPi decreases oxidative stress markers while reducing apoptosis in endothelial and smooth muscle cells (Levi & Stroes, 2008). Furthermore, PARPi diminishes both plaque volume and number, induces favorable structural modifications within plaques, and disrupts plaque progression. Vascular calcification is found to be a powerful and independent risk factor for cardiovascular and cerebrovascular mortality. Yang et al. (2025a) found PARylation level of DNA polymerase gamma were increased in calcified VSMCs from PARP1 activation, led to mitochondrial dysfunction and Adora2a (adenosine receptor A2A)/Rap1 (Ras-associated protein 1) signaling pathway activation to induce VSMC ferroptosis, which ultimately aggravated vascular calcification. PARPi could potentially serve as novel therapeutic strategies for vascular calcification (Yang et al., 2025a).

PARP1 inhibitors mitigate the severity of inflammatory processes across multiple organ systems (Gonzalez-Rey et al., 2007; Moroni, 2008; Mota et al., 2005; Scott et al., 2004; Soriano et al., 2002; Szabó, 2006; Tentori, Portarena & Graziani, 2002). In neurological contexts, these agents reduce cerebral infarction and neutrophil infiltration following transient focal cerebral ischemia (Couturier et al., 2003; Mosca et al., 2011; Tentori, Portarena & Graziani, 2002), confer protection against traumatic brain injury by suppressing nitric oxide overproduction (Wallis, Panizzon & Girard, 1996), alleviate motor deficits, and improve behavioral outcomes (Ding et al., 2001). Furthermore, PARP1 inhibition prevents neurobehavioral and neurochemical abnormalities (Mosca et al., 2011; Sriram et al., 2015), with accumulating evidence establishing their neuroprotective efficacy in diverse central nervous system pathologies (Besson et al., 2003; Jacewicz et al., 2009; Mosca et al., 2011; Nukuzuma et al., 2013). Pharmacologic inhibition of PARP1 by Olaparib rescued NAD⁺ levels and alleviated aging-associated blood–brain barrier (BBB) leakage, and the endothelial Connexin 43 (Cx43)-PARP1-NAD⁺ pathway can combat aging-associated BBB leakage with neuroprotective implications (Zhan et al., 2023).

PARP1 inhibition has been demonstrated to protect against endothelial dysfunction in shock, hypertension, and heart failure (Szabó, 2005; Zakaria et al., 2016). Sirtuins confer multifaceted endothelial protection, and PARP1 hyperactivation-induced endothelial injury involves NAD⁺ depletion that impairs the activity of Sirtuins. Research indicates that PARP inhibitor therapy reduces PARP1-mediated NAD⁺ consumption, suppresses mTOR phosphorylation (Qu et al., 2017), and elevates intracellular NAD⁺ bioavailability for sirtuins. This restores NAD⁺ levels in aged vasculature, enhancing Sirtuin-mediated endothelial protection (Alhosaini et al., 2021). Combined PARP1 inhibition and NAD⁺ augmentation synergistically harness both the anti-aging capacity of SIRT1 pathways and the anti-inflammatory effects mediated through reduced NF-κB activation (Alhosaini et al., 2021; Oliver et al., 1999). Given PARPi’s pivotal role in inflammation and cell death—processes essential for atherosclerotic plaque advancement and rupture—these findings indicate that PARP inhibition may therapeutically intercept these pathological cascades, positioning it as a promising strategy for atherosclerosis management (Oumouna-Benachour et al., 2007).

Beyond the established role of PARP1 in atherosclerosis, emerging evidence suggests that PARP9 and PARP14 also contribute to the pathogenesis of this disease. Iwata et al. (2016) demonstrated that PARP9 and PARP14 are closely associated with interferon-γ (IFNγ) signaling in macrophages. Specifically, PARP9 enhances IFNγ-induced responses, whereas PARP14 suppresses them, thereby establishing a functional balance that shapes vascular inflammation. One of the underlying mechanisms is that PARP9 inhibits PARP14-dependent mono-ADP-ribosylation of signal transducer and activator of transcription 1 (STAT1). The functional balance has important implications for vascular inflammation. Disruption of this equilibrium has significant implications for atherosclerosis (Iwata et al., 2016). Suppression of PARP14 activity promotes macrophage activation and accelerates plaque progression, while silencing PARP9 may alleviate macrophage-mediated vascular inflammation. Although there are currently no specific inhibitors of PARP9, several potent and selective small-molecule PARP14 inhibitors—such as RBN-3143 and Q22—have been developed, with some progressing into clinical trials for inflammatory diseases (Polasek et al., 2025; Wu et al., 2025). However, unlike in cancer or atopic dermatitis where PARP14 inhibition exerts anti-inflammatory effects, PARP14 appears to play a protective, anti-inflammatory role in atherosclerosis. This raises concern that PARP14 inhibition might inadvertently exacerbate vascular inflammation and plaque development. Consequently, the development of PARP9-specific inhibitors and PARP14-specific agonists, combined with advanced strategies for tissue-targeted drug delivery, represents a critical frontier for therapeutic innovation in atherosclerosis.

Impaired energy metabolism, oxidative stress, and dysregulated intracellular signaling pathways play pivotal roles in the pathogenesis of cerebrovascular and cardiovascular diseases. While PARPi exert profound modulatory effects on these processes, their clinical development for cerebrovascular/cardiovascular applications lags significantly behind oncology indications. This disparity stems from incomplete understanding of PARP-involved signaling networks: prior research has failed to delineate sufficiently robust pathways for targeted intervention. Collectively, these emerging lines of evidence underscore the substantial therapeutic potential of PARPi in the management of cardiovascular and cerebrovascular diseases. Beyond their well-established applications in oncology, PARP inhibition can modulate oxidative stress, preserve mitochondrial function, attenuate inflammatory signaling, and prevent energy collapse across diverse ischemic, hypertrophic, and inflammatory pathologies. These findings provide crucial mechanistic insight to guide the rational design of next-generation PARPi optimized for cardiovascular and cerebrovascular indications.

As the field progresses, integrating these mechanistic insights with precision pharmacology, optimized dosing regimens, and disease stage–specific therapeutic windows will be essential for translating PARPi safely and effectively into clinical practice for cardiovascular and cerebrovascular disorders (Fig. 3).