Rewriting the Vascular Script: Epigenetic Modifiers as Scribes of Metabolic Reprogramming in Pulmonary Hypertension

Rewriting the Vascular Script: Epigenetic Modifiers as Scribes of Metabolic Reprogramming in Pulmonary Hypertension | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 26 February 2025 V1 Latest version Share on Rewriting the Vascular Script: Epigenetic Modifiers as Scribes of Metabolic Reprogramming in Pulmonary Hypertension Authors : Runxiu Zheng , Junlan Tan , Xian-ya Cao , Shizhong Wang , Qing Dai , Chao Zhang , Feiying Wang , Jian Yi , Lan Song , and Ai-guo Dai 0009-0003-3038-0358 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174055520.08538882/v1 Published Journal of Molecular Medicine Version of record Peer review timeline 222 views 127 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Pulmonary hypertension (PH) is a fatal cardiovascular disorder characterized by the remodeling of pulmonary vasculature, which serves as a key pathological feature. Treatment options remain constrained, and significant gaps persist in our foundational, clinical, and translational knowledge, thereby necessitating further investigation. Extensive evidence suggests that dysfunction in diverse types of vascular cells plays a critical role in the pathogenesis of PH, with metabolic reprogramming profoundly influencing this process. Nevertheless, the precise molecular mechanisms involved remain poorly understood. Recent studies indicate that epigenetic abnormalities modulate cellular metabolism by altering the gene expression of essential metabolic enzymes, either directly or indirectly. As the role of epigenetics in PH becomes progressively elucidated, it offers promise for establishing a coherent framework for understanding metabolic reprogramming in cells affected by PH. This review concentrates on the alterations in glucose, lipid, and amino acid metabolism of vascular cells within the framework of pulmonary hypertension and delineates the advancements in research concerning epigenetic modifications linked to metabolic regulation in this condition. The reversibility of epigenetic modifications provides the opportunity to rectify their aberrant states. Consequently, targeting epigenetic modifications is considered an appealing therapeutic target for pulmonary hypertension. Finally, we provide a comprehensive summary of the prospects and challenges associated with potential therapeutic strategies for pulmonary hypertension, which are predicated on the reprogramming of vascular cell metabolism via epigenetic modifications. Rewriting the Vascular Script: Epigenetic Modifiers as Scribes of Metabolic Reprogramming in Pulmonary Hypertension Author names Runxiu Zheng 1,3# , Junlan Tan 2,3# , Xianya Cao 1,3 , Shizhong Wang 2 , Qing Dai 3,4 , Chao Zhang 3,4 , Feiying Wang 3,4 , Jian Yi 2,3 , Lan Song 3,4 , Aiguo Dai 3,4,5, * Affliations 1 School of Integrated Chinses and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China 2 The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410021, China 3 Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine, Changsha, Hunan 410208, China 4 School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China 5 Department of Respiratory Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China. * Corresponding author. Corresponding authors at: Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine, Changsha, Hunan 410208, China. E-mail addresses: [email protected] # These authors contributed equally to this work. Funding information National Natural Science Foundation of China, Grant/Award Number: 82370069; Key Research and Development Project of Ningxia Autonomous Region, Grant/Award Number: 2023BEG02033; Major Special Project for High-level Talents of the Health Commission of Hunan Province, Grant/Award Number: R2023097; Hunan Provincial Graduate Student Research Innovation Project, Grant/Award Number: CX20240727. Abstract: Pulmonary hypertension (PH) is a fatal cardiovascular disorder characterized by the remodeling of pulmonary vasculature, which serves as a key pathological feature. Treatment options remain constrained, and significant gaps persist in our foundational, clinical, and translational knowledge, thereby necessitating further investigation. Extensive evidence suggests that dysfunction in diverse types of vascular cells plays a critical role in the pathogenesis of PH, with metabolic reprogramming profoundly influencing this process. Nevertheless, the precise molecular mechanisms involved remain poorly understood. Recent studies indicate that epigenetic abnormalities modulate cellular metabolism by altering the gene expression of essential metabolic enzymes, either directly or indirectly. As the role of epigenetics in PH becomes progressively elucidated, it offers promise for establishing a coherent framework for understanding metabolic reprogramming in cells affected by PH. This review concentrates on the alterations in glucose, lipid, and amino acid metabolism of vascular cells within the framework of pulmonary hypertension and delineates the advancements in research concerning epigenetic modifications linked to metabolic regulation in this condition. The reversibility of epigenetic modifications provides the opportunity to rectify their aberrant states. Consequently, targeting epigenetic modifications is considered an appealing therapeutic target for pulmonary hypertension. Finally, we provide a comprehensive summary of the prospects and challenges associated with potential therapeutic strategies for pulmonary hypertension, which are predicated on the reprogramming of vascular cell metabolism via epigenetic modifications. Key words: pulmonary hypertension; metabolic reprogramming; epigenetic modification; epidrugs Introduction Pulmonary hypertension (PH) is a severe cardiovascular condition characterized by significant pulmonary vascular remodeling [1]. The promotion of pathological vascular remodeling in PH is primarily driven by dysfunction in various cell types within the vessel wall [2]. This dysfunction includes endothelial cell injury, excessive accumulation of smooth muscle cells and fibroblasts due to increased proliferation and migration, and infiltration of perivascular inflammatory cells [3]. Despite these observations, the precise mechanisms remain unclear. Cellular metabolism, which supports growth, reproduction, and normal physiological functions, undergoes alterations during disease states to fulfill proliferative and biosynthetic demands-a process known as metabolic reprogramming. Recent studies have identified metabolic reprogramming as a crucial pathological feature of pulmonary hypertension[4]. Despite substantial research, our comprehension of metabolic reprogramming in pulmonary hypertension remains insufficient. Consequently, it is essential to delineate the precise molecular mechanisms driving this phenomenon to enhance therapeutic approaches for PH. Epigenetics, a concept introduced by Waddington in 1942 [5], encompasses the inheritance of gene expression patterns through chromatin modulation without changing the DNA sequence [6]. It includes mechanisms such as DNA methylation, histone post-translational modifications, non-coding RNAs, chromatin remodeling, and emerging RNA modifications. Essentially, epigenetic modifications influence gene expression by altering the chromatin’s dense and relaxed states, thereby regulating gene accessibility. Epigenetics is pivotal in regulating gene expression, as well as the transcription and translation of proteins, across diverse biological processes. In contrast, pathological states often feature aberrant epigenetic modifications that contribute to disease onset and progression by altering gene expression. In cancer, for instance, it has been documented that epigenetic modifications facilitate tumor growth and progression by reprogramming cellular metabolism through the modulation of key metabolic enzymes [7–9]. As research increasingly reveals the role of epigenetics in pulmonary hypertension [10,11], it is anticipated that this will offer a comprehensive explanation for metabolic reprogramming in this condition. Metabolic reprogramming, due to the critical role in the pathogenesis of PH, has emerged as attracting therapeutic target. Nevertheless, its clinical application is restricted. Recent research increasingly highlights the role of epigenetic modifications in regulating cellular metabolic reprogramming in PH. Thus, proposing targeted therapeutic strategies to address these mechanisms is both warranted and essential. This review provides an overview of recent advancements in understanding metabolic reprogramming and related epigenetic modifications in PH, with the aim of offering new perspectives for clinical treatment approaches. Metabolic reprogramming in PH Glucose metabolism in PH In 1924, Otto Warburg first identified that tumor cells preferentially use glucose to produce lactic acid via glycolysis, regardless of oxygen levels, this phenomenon known as the “Warburg Effect” or “aerobic glycolysis” [12,13]. This effect describes how cells, in response to rapid proliferation demands, opt for the less efficient but faster ATP production of glycolysis over oxidative phosphorylation [13,14]. PH has been likened to a malignant tumor of the cardiovascular system, with studies showing that the Warburg Effect is also present in PH patients and animal models [15–17]. In PH, hypoxia-inducible factor 1-alpha (HIF-1α) and Bone Morphogenetic Protein Receptor Type 2 (BMPR2) are critical in driving glucose metabolism reprogramming. HIF-1α, a transcription factor active under hypoxic conditions, regulates several glycolysis-related genes, including Glucose transporter 1 (GLUT1), Hexokinase 2 (HK2), Phosphofructokinase 1 (PFK1), Pyruvate kinase isozyme typeM2 (PKM2), Lactate Dehydrogenase A (LDHA), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), and 3-Phosphoinositide-Dependent Protein Kinase (PDK) [18–24]. Increased HIF-1α expression and activity have been observed in the pulmonary arteries of PH patients and in PH animal models, often associated with upregulation of Pyruvate PDK4 in pulmonary arterial smooth muscle cells (PASMCs) or HK2 in pulmonary arterial endothelial cells (PAECs), leading to endothelial dysfunction and impaired angiogenesis [25–29]. BMPR2, a transmembrane serine/threonine kinase, is linked to increased susceptibility to PH through mutations that induce a glycolytic phenotype and enhance the pentose phosphate and polyamine biosynthesis pathways [30–32]. Research by Isabel et al. has connected mitochondrial function to BMPR2 signaling in PAECs, suggesting that combined hypoxia and BMPR2 dysfunction impair mitochondrial adaptation, contributing to PH progression [33]. Reflecting the Warburg Effect, positron emission tomography (PET) with 18F-FDG, a glucose analog, has been employed to visualize metabolic changes. Studies have shown elevated FDG uptake in the lungs of PH patients compared to controls, with increased FDG uptake correlating with higher right ventricular systolic pressure and pulmonary vascular resistance [33,34]. Furthermore, Sumer et al. found that elevated FDG uptake in the right atrium and right ventricle correlates with pulmonary hypertension and with mean pulmonary artery pressure (mPAP) and right atrial pressure (RAP), respectively [35]. However, the utility of FDG-PET for diagnosing or predicting PH prognosis requires further investigation. Lipid metabolism in PH Lipids are diverse and structurally complex molecules with various biological functions. They serve as crucial energy sources and storage materials, provide essential fatty acids and their derivatives, and act as structural components of biological membranes and signaling molecules within cells. In mammals, lipids primarily circulate in the form of free fatty acids and are taken up by cells via membrane proteins such as fatty acid-binding protein (FABP) and platelet glycoprotein 4 (CD36). They are then transported to the mitochondria through carnitine/acylcarnitine translocase (CAT), where carnitine palmitoyl transferase 2 (CPT2) converts them into long-chain acyl-coenzyme A, entering the fatty acid β-oxidation pathway and producing acetyl-coenzyme A. In 1963, Randle et al. [36] proposed the “glucose-fatty acid cycle,” describing how increased acetyl-coenzyme A from fatty acid oxidation inhibits pyruvate dehydrogenase, thus reducing glucose oxidation. Conversely, increased acetyl-coenzyme A from glycolysis inhibits fatty acid oxidation by interfering with 3-ketoacyl coenzyme A sulfurylase and other mitochondrial enzymes, forming the “Randle cycle.” In PH, the metabolic shift towards aerobic glycolysis inhibits fatty acid oxidation [37]. Concurrently, elevated expression of CD36 and CPT1 enhances lipid uptake by cells, leading to lipid accumulation in cardiopulmonary tissues and blood vessels [38–42]. This lipid accumulation increases the concentration of free fatty acids in the blood [37,43,44], highlighting the role of lipid metabolism reprogramming in PH pathogenesis. Coursen et al. [45] demonstrated that lipid metabolism abnormalities are prevalent in systemic sclerosis with concurrent PH, and that elevated plasma free fatty acids are an independent predictor for PH, potentially aiding early disease diagnosis. In summary, impaired lipid metabolism in PH results in lipid accumulation in the circulation, underscoring the potential role of lipid-lowering drugs in mitigating the PH phenotype. Niacin, a commonly used lipid-lowering medication, has been shown to improve PH progression in Sugen5416-combined hypoxia-induced mouse models and wild-type lysergic acid-induced rat models by inhibiting pulmonary vascular remodeling [46]. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) are key carriers of lipids in the bloodstream. Dysregulation of LDL and HDL has been observed in PH patients [41,47], with significantly reduced HDL levels correlating with clinical severity. Huang et al. [48]identified apolipoprotein A-I (Apo A-I) as the most critical protein differentially expressed in PH patients, noting that lower Apo A-I levels are an independent risk factor for PH and have strong predictive value for late mortality. The Apo A-I mimetic peptide 4F demonstrated efficacy in rescuing rat and mouse models of PH induced by monocrotaline(MCT) and hypoxia, respectively [41,49] Amino acid metabolism in PH Aerobic glycolysis provides rapid energy to highly proliferating cells but detaches glucose from the tricarboxylic acid cycle (TCA), necessitating a continuous supply of carbon intermediates for TCA function. Amino acid metabolism, particularly glutamine metabolism, is one such pathway. Glutamine serves as a crucial metabolic fuel, supplying carbon and nitrogen to rapidly proliferating cells. Recent studies have reported increased glutamine levels in the serum and pulmonary arteries of patients with idiopathic pulmonary arterial hypertension (IPAH) [50,51], heightened glutamine uptake by pulmonary arterial endothelial cells (PAECs) [51], and elevated expression and activity of glutaminase [52,53]. These changes support enhanced glutamine catabolism, meeting the demands of excessive cell proliferation and driving pulmonary vascular remodeling and experimental PH. Additionally, elevated levels of the transporter proteins SLC1A5, glutamine, and glutamate have been observed in the right ventricular tissues of an MCT-induced rat model of PH, indicating concurrent enhanced glutamine metabolism in the right ventricle [54]. Arginine, an essential amino acid, is a substrate for both nitric oxide synthase and arginase. Arginase produces urea and ornithine, which provide carbon intermediates for the TCA cycle, while nitric oxide synthase produces nitric oxide and citrulline, with nitric oxide acting as a potent vasodilator. Studies have shown that arginine bioavailability influences nitric oxide production [55], and both nitric oxide and nitric oxide synthase are deficient in PH [56,57]. Furthermore, Simpson et al. demonstrated an upregulation of the kynurenine metabolic pathway in PH. Clinical data suggest that higher kynurenine/tryptophan ratios measured two years before diagnostic right heart catheterization increase the likelihood of comorbid PH in systemic sclerosis (SSc), with elevated ratios predicting PH development and mortality [58]. Pi et al. [59] analyzed data from a prospective cohort of PH patients and found associations between polyamine and histidine metabolic pathways and variations in right ventricular dilation, mortality, N-terminal B-type natriuretic peptide levels, REVEAL scores, and 6-minute walk distance. These findings suggest that these pathways may serve as promising biomarkers for identifying high-risk patients. In summary, PH is characterized by excessive proliferation of vascular cells. To meet their energy and biosynthetic needs, these cells undergo metabolic reprogramming, which, in turn, influences disease progression by altering their phenotype (Fig. 1). Epigenetic modifications regulate metabolic reprogramming in PH DNA methylation regulates cellular metabolic reprogramming in PH DNA methylation entails the transfer of a methyl group from S-adenosylmethionine (SAM) to the 5-carbon position of cytosine residues within CpG dinucleotides, a process mediated by DNA methyltransferases (DNMTs). Once methylated, CpG islands can inhibit gene expression either by obstructing the binding of transcriptional regulators and the recruitment of transcription factors or by attracting protein complexes that alter chromatin structure. Conversely, 5-methylcytosine (5mC) undergoes progressive oxidation by TET proteins, leading to the gradual removal of the methylation ”cap” and the subsequent reactivation of gene expression. DNA methylation is critical for preserving normal cellular function, maintaining genomic stability, and supporting embryonic development. However, aberrant DNA methylation patterns are increasingly associated with the onset and progression of various diseases. Ulrich et al. [60] identified altered DNA methylation profiles in patients with PH through an epigenome-wide association study (EWAS), noting hypermethylation of histone Z (CTSZ), conserved oligomer Golgi complex 6 (COG6), and zinc-finger protein 678 (ZNF678), with BMP10 also hypermethylated among 16 PH-related genes. In PH, DNA methylation is crucial for regulating the expression of key mitochondrial antioxidant enzymes, such as superoxide dismutase 2 (SOD2) and bone morphogenetic protein receptor 2 (BMPR2). Reduced SOD2 expression has been linked to spontaneous PH, with decreased SOD2 levels observed before PH onset [61]. In lung tissues from PH patients and rats, increased expression of DNMT1 and DNMT3B correlates with epigenetic silencing of the SOD2 gene, due to CpG island hypermethylation in the promoter and enhanced region of intron 2. This alteration disrupts H 2 O 2 -mediated redox signaling, activates HIF-1α, and contributes to a pro-proliferative and anti-apoptotic phenotype in PASMCs [62]. BMPR2, a member of the transforming growth factor β (TGF-β) family, exhibits promoter hypermethylation, a significant factor in hereditary PH prevalence [63]. Bisserier et al. [64] found BMPR2 promoter hypermethylation in IPAH patients via targeted bisulfite sequencing. The low BMPR2 expression in lung tissues was associated with downregulation of the transcriptional regulator SIN3a, which inhibits PASMCs proliferation and migration by upregulating TET1 and downregulating DNMT1, thereby reducing BMPR2 methylation. This evidence supports SIN3a as a potential therapeutic target for clinical PH. Fatty acid metabolic reprogramming in PH is linked to DNA methylation. Liu et al. [65] developed a mouse model of pulmonary hypertension (PH) using PM2.5 and identified a CpG island in the promoter region of the ELK3 gene. They found that PM2.5 exposure increased DNA methyltransferase activity, leading to elevated DNA methylation and reduced ELK3 protein expression. This reduction disrupted mitochondrial dynamics, impairing fatty acid β-oxidation and resulting in increased expression of the fatty acid transporter protein FABP3. Consequently, FABP3’s uptake ability was enhanced while its catabolic activity was reduced, causing lipid accumulation in PASMCs. This accumulation contributed to a synthetic PASMC phenotype and resulted in elevated pulmonary artery pressure, pulmonary vasculature remodeling, right ventricular hypertrophy, and progression to PH. Additionally, DNA methylation affects cellular glucose metabolism in PH. Tian et al. [66] demonstrated that elevated DNMT1 expression in a rat model induced by MCT activates HIF-1α by inhibiting SOD2, which suppresses oxidative phosphorylation and enhances aerobic glycolysis through activation of pyruvate dehydrogenase kinase 1 (PDK1). This metabolic shift ultimately leads to a fibrotic phenotype due to excessive proliferation of right ventricular fibroblasts. (Fig. 2) Histone modification regulates cellular metabolic reprogramming in PH Chromatin is the structural form of DNA that is tightly packed within the cell nucleus, with the nucleosome being its fundamental unit. Each nucleosome consists of an octamer of four core histones—H3, H4, H2A, and H2B—each with positively charged lysine residues that interact with the negatively charged DNA backbone. This interaction facilitates the compact organization of chromosomes. Despite the generally dense packaging of DNA in the nucleus, it must remain accessible for processes such as transcription and replication. Histones extend beyond the nucleosome through their tails, and many of these tail residues undergo post-translational modifications, including methylation, acetylation, phosphorylation, and ubiquitination. These histone modifications play a crucial role in regulating DNA accessibility. Histone methylation Similar to DNA methylation, histone methylation involves the transfer of methyl groups to specific amino acid residues on histones, predominantly lysine and arginine of histones H3 and H4. This process modulates gene expression by either activating or repressing it, depending on the specific residues methylated and the number of methyl groups added. Histone methyltransferases (HMTs) and histone demethylases (HMDs) meticulously regulate this dynamic modification process. Zeste enhancer homolog 2 (EZH2) is a histone methyltransferase significantly elevated in PASMCs from patients with chronic thromboembolic pulmonary hypertension and in hypoxia-induced rodent models. EZH2 promotes cell proliferation, migration, and an anti-apoptotic phenotype [67,68]. Proteomic analyses have revealed that EZH2 also enhances the expression of glutamine-dependent biosynthesis factors GLS and GLUD1, as well as TCA cycle factors SDHA and OGDH. This suggests that EZH2 supports oxidative phosphorylation and energy production by facilitating glutamine metabolism. Mitochondrial function assessments confirmed that EZH2 inhibition markedly reduces the glycolytic capacity of PASMCs in PH, indicating that targeting EZH2 may improve pulmonary vascular remodeling in PH [69]. G9a, another histone methyltransferase, catalyzes mono- or bis-methylation of H3K9 and is involved in PASMCs proliferation, migration, and contractile alterations in sheep fetal lung models [70]. Elevated levels of G9a and its chaperone protein GLP have been observed in PH patients and rodent PH models. G9a inhibits the expression of cholesterol synthesis-related genes such as Srebf2, Hmgcs1, and Dhcr24, leading to intracellular lipid droplet accumulation and a pathological PASMC phenotype. Pharmacological inhibition of G9a in experimental PH models effectively reduces lung vascular remodeling and improves cardiopulmonary hemodynamics and right heart function, suggesting that targeting G9a/GLP may be a viable therapeutic approach for clinical PH [71]. Nuclear receptor binding SET domain 2 (NSD2), a member of the histone methyltransferase family, catalyzes lysine methylation on histones, affecting DNA accessibility. Zhou et al. [72] demonstrated that NSD2 mediates demethylation of H3K36 in experimental PH models and regulates metabolic pathways impacting PH development. Silencing NSD2 improved right ventricular function and reversed pulmonary vascular remodeling in MCT-induced rat models. JMJD1C, a histone demethylase, is elevated in hypoxia-induced mouse lung tissues and promotes glycolytic enzyme expression through STAT signaling. Zhang et al. [73] found that JMJD1C upregulates HK2, PGK1, and LDHA, and its inhibition ameliorates hypoxia-induced PASMC proliferation and pulmonary vascular remodeling by impairing glycolytic processes (Fig. 3). Histone acetylation Histone acetylation involves the transfer of acetyl groups from acetyl coenzyme A to lysine residues on histone tails, a process catalyzed by histone acetyltransferases (HATs). This modification neutralizes the positive charge of lysine residues, leading to chromatin relaxation and enhanced gene transcription. Conversely, histone deacetylases (HDACs) remove acetyl groups from lysine residues, restoring chromatin density and repressing gene expression. This dynamic balance between HATs and HDACs regulates chromatin structure and gene activity in cells. Histone acetylation levels were found to be reduced in fetal sheep PASMCs exposed to prolonged hypoxia at high altitude compared to those at sea level [74]. However, HDAC inhibitors were effective in ameliorating the PH phenotype in both animal models and cellular models of PH [75–77], suggesting that modifications in histone acetylation may influence phenotypic changes in various vascular cells in PH. Xing et al. [78] demonstrated that lysine acetyltransferase 7 (KAT 7) is recruited to the promoter of HIF-1α, acetylating H4K5 to enhance its expression, which contributes to the development of PH. HIF-1α is a crucial regulator of hypoxia-induced PH and a key transcription factor for several glucose metabolism-related enzymes, indicating that histone acetylation may play a significant role in cellular metabolic reprogramming. Li et al. [79] reported that increased β-catenin activity in PASMCs led to elevated transcription of aldehyde dehydrogenase(ALDH1A3), facilitating the generation of acetyl-coenzyme A. This process resulted in acetylation of H3K27 by acetyltransferase KAT2B, creating an active enhancer at the binding site of the NFYA transcription factor, which drives cell proliferation and a glycolytic phenotype. Yu et al. [80] found that hypoxia inhibits BOLA3 transcription through HDAC1-mediated reduction of H3K9 acetylation. BOLA3 deficiency activates glycine metabolism via glycine cleavage system protein H and upregulates glycolysis and fatty acid oxidation by disrupting iron-sulfur cluster integrity and mitochondrial complex protein levels, leading to pro-proliferative and anti-apoptotic phenotypes in PAECs. Conversely, in outer membrane fibroblasts in PH, HDAC inhibitors SAHA and Apicidin reduce purine metabolism synthesis by inhibiting serine metabolism and the pentose phosphate pathway[81]. Additionally, Plecita et al. [82] observed a significant decrease in phosphorylated pyruvate dehydrogenase (PDH) expression, a shift towards aerobic glycolysis, and enhanced proliferation in CD4+ T cells exposed to the outer membrane fibroblasts. This study highlighted that cytokines and metabolites from these fibroblasts promote T cell polarization by reprogramming glucose metabolism, which induces localized inflammation and pulmonary vascular remodeling. Notably, the HDAC class I inhibitor SAHA effectively reversed these effects (Fig. 4). Other types Histone modification In addition to the well-studied histone methylation and acetylation, post-translational modifications such as lactylation, phosphorylation, succinylation, and SUMOylation can also occur on the N- and C-terminal regions of histones. Chen et al. [27] demonstrated that hypoxic conditions lead to the accumulation of mitochondrial reactive oxygen species (mROS), which inhibit the hydroxylation of HIF-1α, thereby maintaining its stability and increasing the expression of PDK1 and PDK2. This results in enhanced aerobic glycolysis in PASMCs and increased lactate production. The lactate provides lactoyl groups that modify histone H3 at lysine 18 (H3K18), ultimately promoting PASMCs proliferation and contributing to the development of hypoxic pulmonary hypertension. Non-coding RNA regulates cellular metabolic reprogramming in PH Non-coding RNA refers to RNA molecules that are not translated into proteins. This category includes microRNAs (miRNA), long non-coding RNA (lncRNA), and circular RNAs (circRNA). The role of non-coding RNA in PH has been increasingly elucidated (Fig. 5). miRNA MicroRNA (miRNA) is endogenous, non-coding RNAs approximately 22 nucleotides long that regulates target gene expression at the post-transcriptional level by either inhibiting translation or promoting mRNA degradation. Increasing evidence suggests that miRNA plays an essential role as regulatory element in various biological processes, including cellular differentiation and development, metabolism, proliferation, and apoptosis. The role of miR-124 in metabolic reprogramming in PH has been extensively studied. Wang et al. reported that miR-124 was downregulated in pulmonary artery fibroblasts from PH patients and calves with hypoxic pulmonary hypertension, affecting fibroblast proliferation and migration through its target- PTBP1 [83]. Caruso et al. further demonstrated that BMPR2 mutations or deletions resulted in reduced miR-124 levels, leading to increased PTBP1 expression, which in turn elevated PKM2 levels and decreased PKM1 levels. This altered splicing of PKM transcripts was associated with increased glycolysis and a hyperproliferative phenotype in PH patient-derived endothelial cells [84]. Zhang et al. confirmed that in human and calf pulmonary artery fibroblasts, downregulation of miR-124 led to increased PTBP1 levels and changes in PKM splicing, which promoted a glycolytic phenotype and enhanced proliferation and peripheral inflammation [85]. Additionally, Luo et al. found that miR-125a-5p was significantly reduced in a rat model of PH induced by MCT. They demonstrated that miR-125a-5p negatively regulates HK2 expression in PASMCs, with its reduction leading to increased glycolysis and proliferation of PASMCs, and contributing to pulmonary vascular remodeling [86]. Hong et al. observed upregulation of miR-138 and miR-25 in PH, which was linked to downregulation of mitochondrial calcium uniporter (MCU) and subsequent mitochondrial dysfunction, PDH inhibition, and altered glucose oxidation, promoting PASMCs migration, proliferation, and apoptosis resistance [87]. Tian et al. found that downregulation of miR-148b-3p in RV fibroblasts from PH models and patients led to a shift from oxidative phosphorylation to aerobic glycolysis by inhibiting SOD2 expression, resulting in a fibrotic cell phenotype [66]. Furthermore, Niu et al. discovered that miR-22-3p regulates PASMCs proliferation and vascular remodeling by modulating lipid metabolism [88]. Additionally, the PPARγ agonist pioglitazone was shown to reverse mitochondrial fibrosis and prevent lipid deposition in cardiomyocytes, effectively countering pulmonary hypertension and heart failure in the rat model by restoring mitochondrial fatty acid metabolism [89]. lncRNA Long non-coding RNA (lncRNA) is a class of non-coding RNAs exceeding 200 nucleotides in length, synthesized by RNA polymerases. These molecules engage in a multitude of biological processes through interactions with DNA, RNA, and proteins. lncRNA plays a crucial role in regulating chromatin structure and function, modulating the transcription of both proximal and distal genes, and affecting RNA splicing, stability, and translation. Growing evidence indicates that lncRNA is involved in pulmonary vascular remodeling and the development of PH [90–92]. However, their regulatory roles in cellular metabolic reprogramming and their functional mechanisms in PH remain underexplored. HIF-1α, a key mediator in PH pathogenesis, is significantly influenced by lncRNA. Chen et al. reported that lncRNA FAM83A-AS1 competes with p-VHL for binding to HIF-1α, thereby inhibiting VHL-mediated ubiquitination and proteasomal degradation, which leads to HIF-1α accumulation [93]. The newly identified lncRNA HITT disrupts HIF-1α translation and expression by sequestering YB-1 from the 5’-UTR of HIF-1α mRNA via a YB-1 binding motif[94]. Additionally, lncRNA H19 enhances HIF-1α expression by recruiting EZH2 to trimethylate histone H3K4 [95]. Beyond affecting HIF-1α expression, lncRNA also contributes to HIF-1α protein stability. For instance, lncRNA MTA2TR improves HIF-1α stability by promoting its deacetylation [96]. Wang et al. demonstrated that lncRNA PVT1 acts as a scaffold for the chromatin modifier KAT2A, which acetylates H3K9 and recruits TIF1β, thereby stabilizing HIF-1α and enhancing NF90 transcription [97]. Furthermore, lncRNA HIFCAR binds directly to HIF-1α, facilitating its recruitment along with the cofactor p300 to target gene promoters, thus elucidating the mechanism of lncRNA-mediated activation of HIF-1α [98]. HIF-1α, as a major regulator of hypoxic stress, activates glucose transport proteins and glycolytic enzymes through gene transcription, playing a significant role in metabolic reprogramming. Given this, we propose that lncRNA may play a significant regulatory role in metabolic reprogramming in PH via HIF-1α. This regulation could occur through mechanisms such as enhancing protein translation and stabilization, inhibiting protein degradation, thereby leading to HIF-1α accumulation, or facilitating the activation of HIF-1α. Other types of ncRNA Circular RNA (circRNA) is a single-stranded, covalently closed RNA molecule that can function as a transcriptional regulator, miRNA sponge, and protein scaffold. Lu et al. [99] first reported that reduced circSMOC1 in the nucleus facilitates the specific splicing of PK by PTBP1, leading to elevated expression of PKM2. Concurrently, decreased cytoplasmic circSMOC1 inhibits the translation of pyruvate dehydrogenase E1 subunit β (PDHB) by limiting miR-329-3p adsorption, resulting in enhanced aerobic glycolysis and hyperproliferation of PASMCs. PIWI-interacting RNA (piRNA) is a kind of small non-coding RNA that forms silencing complexes in the reproductive system to protect genome integrity by silencing transposable elements. Emerging evidence has revealed their roles in human infertility, cancer, and neurological disorders [100,101]. Acyl coenzyme A, an enzyme crucial for mitochondrial fatty acid β-oxidation, catalyzes the dehydrogenation of fatty acyl coenzyme A esters. Cui Ma et al. [102] discovered differential expression of piRNA in rat model of HPH compared to control group. Elevated piRNA-63076 expression interacted with Acadm, increasing methylation of its CpG site and decreasing its expression, which in turn promoted the proliferation of PASMCs. RNA modifications regulate cellular metabolic reprogramming in PH In 2011, Jia et al. [103] demonstrated that RNA methylation is a reversible process involved in gene expression regulation, thereby establishing the field of RNA epigenetic modification. Aberrant RNA modifications can disrupt cell survival, proliferation, differentiation, invasion, and stress adaptation by affecting RNA splicing, maturation, translocation, stability, and translation. Recent studies have highlighted the critical role of dysregulated RNA modifications in cardiovascular disease development [104]. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, occurring at the sixth nitrogen position of adenosine. Elevated levels of m6A have been observed in PH patients and animal models [105–107]. This modification promotes pulmonary vascular remodeling by facilitating the proliferation of PASMCs [108,109], focal cell death, proliferation, and endothelial-to-mesenchymal transition of PAECs [110–112], as well as inflammation and oxidative stress in lung macrophages [113], revealing its novel role in PH pathogenesis. m1A modification, a reversible methylation occurring at the first nitrogen atom of the adenine base in RNA, plays a crucial role in RNA metabolism, normal physiological functions, and disease states. Zhang et al. [114] first identified that ADAR1 may contribute to PASMCs proliferation by mediating m1A modification. As RNA modification is a recent focus in epigenetic research, its abnormality is associated with PH development, yet its role in regulating cellular metabolic reprogramming warrants further investigation. Existing “Epidrugs” for PH therapeutic potential As evidence mounts regarding the critical role of epigenetic modifications in PH, a dynamic and variable process, numerous studies have sought to counteract pulmonary vascular remodeling by normalizing these modifications. The advent of ”epidrugs” marks a new era, with the potential to advance precision medicine in PH by targeting deleterious genetic changes through epigenetic proteins and non-coding RNA (Table 1). A study by Bisserier et al. [65] demonstrated the protective role of SIN3A in PH. Therapeutic intrapulmonary delivery of SIN3A reduced the methylation of the BMPR2 promoter region by upregulating TET1 and DNMT1 activities, effectively ameliorating pulmonary artery pressure and reversing pulmonary vascular and cardiac remodeling in rodent models of PH. This highlights a novel therapeutic approach involving SIN3A gene therapy for PH through the regulation of epigenetic modifications of pulmonary vascular genes. Xing et al. [61] explored 5-Aza-2’-deoxycytidine (5-Aza-dC), a DNMT inhibitor, to investigate its effects on hypoxic pulmonary hypertension. They found that 5-Aza-dC inhibited DNMT levels in a dose-dependent manner, thereby reducing PTEN methylation and promoting PTEN protein expression. This inhibition of PTEN methylation led to decreased proliferation and migration of PASMCs. In vivo studies further confirmed that 5-Aza-dC increased PTEN expression in the lungs of HPH rat models, reduced mean pulmonary artery pressure, and decreased the right ventricular hypertrophy index, demonstrating its therapeutic potential for alleviating HPH through PTEN promoter demethylation. Additionally, Joshi et al. [115] revealed that glucose-6-phosphate dehydrogenase (G6PD) acts as a metabolic reprogramming agent and links aberrant gene regulation with PH pathogenesis. G6PD knockdown or inhibition using NED reversed the PH phenotype in mice by inhibiting cell growth through increased TET2 expression, which promoted hypomethylation of promoter-flanking regions of target genes and reduced hypoxia-induced changes in cytoplasmic and mitochondrial metabolism. HDAC inhibitors are a potent class of anticancer drugs, and their therapeutic potential in PH has gained increasing attention in recent years. Butyrate, a four-carbon short-chain fatty acid, inhibits class I and II HDACs and plays a significant role in epigenetic regulation. Research indicates that butyrate supplementation in drinking water reduces right ventricular systolic pressure and hypertrophy and alleviates pulmonary vascular remodeling in a hypoxia-induced PH model in rats [116]. Zhao et al. [78] found that HDAC inhibitors, such as valproic acid and octane diy laniline hydroxy valeric acid, mitigated the development of hypoxia-induced PH in rats, supporting the use of HDAC inhibitors as a therapeutic strategy for PH. Nozik-Grayck et al. [117] provided evidence that class I HDAC3 activity enhances SOD3 expression and promotes PASMCs proliferation in PH, while its inhibitor MGCD0103 offers protection by reversing this effect. Apicidin, another HDAC inhibitor, modulates the expression of pro-oxidant and antioxidant enzymes, preventing phenotypic changes in PASMCs in neonatal sheep[118]. Inactivation of the deacetylase SIRT exacerbates hypoxia-induced vascular and cardiac remodeling in rodents; however, its activator Stac-3 effectively inhibits PASMCs proliferation by restoring histone acetylation/deacetylation balance and mitochondrial function, delaying PH progression [119]. BRD4, a member of the BET family of epigenetic regulators, influences gene expression by binding to acetylated histone tails. The BRD4 inhibitor JQ1, administered via nebulization, successfully ameliorated the Sugen5416 plus hypoxia-induced PH phenotype in rats [120]. The BET inhibitor RVX208 has been shown to prevent hyperproliferation of microvascular endothelial and smooth muscle cells from PH patients and reverse pulmonary vascular remodeling and hemodynamic changes in PH rats [121]. Additionally, Apabetalone, a clinically available BRD2-4 inhibitor, demonstrated reduced pulmonary vascular resistance and improved hemodynamic parameters in a single-group, open-label study by Provencher et al. [122]. Although further investigation is needed to determine whether these effects are directly related to pulmonary vascular remodeling, the study confirms the feasibility and good clinical tolerability of Apabetalone for treating PH. Non-coding RNA represents a promising target for modulating epigenetic modifications. Research indicates that the PPARγ agonist pioglitazone regulates miRNA networks to correct lipid metabolism disorders and mitochondrial dysfunction in the pulmonary vasculature. This modulation helps reverse severe PH and vascular remodeling, and prevents right ventricular failure, thus offering a new therapeutic strategy for PH through the regulation of epigenetic modifications that affect metabolic reprogramming. Specifically, in right ventricular tissue, miR-197 and miR-146b were upregulated, while miR-133b was downregulated in peripheral pulmonary arteries, and miR-133b was upregulated while miR-146b was downregulated in plexiform vasculopathy [89]. Galkin et al. [123] observed that miR-135a-5p and miR-146a-5p levels were reduced in Seralutinib-treated lungs, correlating with elevated BMPR2 levels, suggesting that miRNAs contribute to altered BMPR2 expression following Seralutinib treatment, demonstrating robust efficacy in rodent models. Additionally, miR-204 was downregulated in PASMCs from PH patients and animal models, but its delivery to the lungs of PH animals significantly improved disease severity [124]. Moreover, intravesical delivery of mesenchymal stromal cell-derived exosomes (MEX) reduced vascular remodeling and hypoxic PH by increasing miR-204 levels in lung tissue [125], highlighting miR-204 as a potential target for PH treatment. Limitations of Current Research and Challenges for Future Investigations Metabolic reprogramming and epigenetic modifications play significant roles in the development of PH and represent promising targets for treatment. Dichloroacetate (DCA), a drug targeting the metabolic enzyme PDK used for treating cancer and congenital mitochondrial diseases [126–128], was investigated by Michelakis et al. in a series of studies and an exploratory open-label phase I clinical trial involving patients with IPAH. While the treatment improved hemodynamic and functional capacities, the responses varied among individuals [129]. Although metabolic reprogramming is a key pathological feature of PH, no definitive and effective metabolic therapy has been established due to metabolic heterogeneity among different cell types and disease stages, as well as the lack of drug specificity, which can lead to systemic effects and unacceptable toxic side effects. Recent studies have increasingly demonstrated that aberrant epigenetic modifications can regulate metabolic reprogramming by modulating the expression of transporter proteins and metabolic enzymes. The reversibility of these modifications provides an opportunity to correct their abnormal states. Consequently, targeting epigenetic modifications to address metabolic reprogramming is emerging as a crucial strategy for PH treatment. However, despite the appeal of targeting epigenetic modification-associated proteins, they often lack specificity, affecting all cell types and all genomic loci within a uniform cell. Thus, developing precision-targeted therapeutic strategies for specific genomic loci holds significant scientific and clinical value. The interplay between epigenetics and metabolic reprogramming is a dynamic and intricate bidirectional interaction. Altered metabolic patterns can impact the homeostasis of epigenetic modifications. Metabolites such as S-adenosylmethionine, acetyl coenzyme A, lactate, and succinyl coenzyme A, produced through glycolysis, the TCA cycle, fatty acid oxidation, and amino acid metabolism, provide methyl, acetyl, lactoyl, and succinoyl groups for DNA and histone modifications, respectively [130–133]. Additionally, α-ketoglutarate, a crucial metabolite and cofactor for the JmjC domain-containing demethylase family and TET DNA cytosine oxidase [134,135], influences DNA and histone methylation levels. PPARγ, a ligand-activated transcription factor, and its agonist pioglitazone, act as metabolic regulators by modulating the miRNA network in the right ventricle, peripheral pulmonary arteries, and plexiform vascular lesions, restoring mitochondrial fatty acid oxidation, and preventing intracellular lipid accumulation [89]. G6PD, a key enzyme in the pentose phosphate pathway, regulates DNA methylation levels by influencing TET2 activity. Its inhibitor, NEDOU, shows effective therapeutic potential in a PH mouse model by modulating DNA methylation and reprogramming glucose metabolism [115]. Understanding the intricate relationship between epigenetic modifications and metabolic reprogramming is essential for elucidating the molecular mechanisms underlying pulmonary hypertension. Further research into this interaction could pave the way for novel therapeutic strategies and biomarkers for this complex disease. Recent research using animal models and cell studies has identified numerous epigenetic targets for PH, but translating these findings into clinical practice remains challenging. Epigenetic modifications are widespread across physiological processes, and indiscriminate inhibition or deactivation of related proteins can cause significant harm to the organism. Therefore, selectively targeting affected tissues and cells in pathological conditions is a promising area for future research. Nanomedicine has recently attracted considerable attention, with ongoing studies exploring its application in PH. Victor et al. utilized nanoparticles to deliver rapamycin to remodeled pulmonary vasculature, achieving reduced systemic side effects and more effective reversal of cardiac and pulmonary remodeling compared to rapamycin alone. This demonstrates the potential of nanoparticles for targeted delivery in reversing PH development[136]. Additionally, Li et al. developed glucuronic acid-modified liposomes (GlcA-Lips) to target GLUT-1 and deliver sildenafil to over-proliferated PASMCs, successfully inhibiting the MCT-induced PH model in rats [137]. Several miRNAs involved in pulmonary vascular remodeling have been identified as potential therapeutic targets for PH in clinical and experimental settings. However, RNAi-based therapies face limitations such as challenges in targeted delivery, off-target effects, and toxicity. Studies have shown that lipid nanoparticles delivering miRNA-145 inhibitors effectively mitigate new pulmonary vascular remodeling without causing detectable renal, hepatic, cardiac, metabolic, or hematological toxicity [138]. Thus, combining nanotechnology-based drug delivery systems with epidrugs, which enable passive accumulation of drugs and carriers at targeted sites, offers a promising approach for more precise drug delivery and presents new opportunities for targeted therapy in PH. Given the crucial role of epigenetic regulation, the precise manipulation of epigenomic target sites within cells is vital for treating PH. In contrast to small molecules that broadly inhibit specific epigenetic factors, CRISPR-based epigenomic editing offers a more targeted therapeutic approach. Successful outcomes have been reported using epigenomic editing for gene activation and repression in animal models of various diseases [139–141], which informs potential treatments for PH. However, clinical application of this approach faces challenges including in vivo delivery, gene expression persistence, treatment timing and dosage, and the specificity of editing tools. Notably, a 2024 study in Nature demonstrated that lipid nanoparticles delivering mRNA encoding EvoETRs to the mouse liver achieved durable and heritable epigenetic silencing of Pcsk9. This study supports the feasibility of transient ETR delivery for sustained in vivo epigenetic silencing and establishes a foundation for developing in vivo epigenetic therapies [142]. Perspectives and Conclusion Metabolic reprogramming and aberrant epigenetic modifications are pivotal pathological features of PH. Aberrant epigenetic modifications disrupt the regulation of key metabolic enzyme gene expression, thereby driving metabolic reprogramming in vascular cells that sustains their pathological phenotype. Conversely, abnormal metabolic byproducts also perturb the equilibrium of epigenetic modifications. These interrelated pathological processes synergistically induce vascular cells to rapidly and persistently adapt to adverse environments, ultimately leading to pathological vascular remodeling. Although the clinical efficacy of drugs targeting metabolism has been limited, the dynamic nature of epigenetic modifications makes them promising candidates for therapeutic intervention aimed at reversing metabolic reprogramming and pulmonary vascular remodeling. Considerable evidence indicates that HDAC inhibitors may be effective anti-cancer agents, particularly when used in conjunction with conventional chemotherapeutics, presenting substantial potential for epigenetic therapies in PH. Despite these prospects, current research is largely restricted to cellular and animal models. Traditional epigenetic therapies encounter significant challenges in targeted application, complicating their clinical use. Thus, comprehensive and rigorous research is urgently required to validate their specificity, efficacy, and safety prior to clinical application, which is essential for the advancement of precision epigenetic therapeutic strategies. In summary, this review offers a comprehensive examination of metabolic reprogramming in vascular cells associated with PH, emphasizing the critical regulatory role of epigenetics in metabolic processes. Furthermore, it introduces promising precision epigenetic therapeutic strategies aimed at advancing clinical management of PH. Author Contributions Runxiu Zheng and Junlan Tan were co-first authors who contributed equally to this article. Runxiu Zheng and Junlan Tan made substantial contributions to the conception and design of the review, as well as drafting the manuscript. Shizhong Wang, Xianya Cao and Chao Zhang were responsible for the collection and analysis of the literature. Qing Dai, Feiying Wang, and Lan Song provided critical revisions of important intellectual content in the manuscript. The corresponding author, Aiguo Dai, coordinated various aspects of the work and gave final approval for publication. Acknowledgements This work was supported by grants from National Natural Science Foundation of China (82370069), Key Research and Development Project of Ningxia Autonomous Region (2023BEG02033)， Major Special Project for High-level Talents of the Health Commission of Hunan Province (R2023097), Hunan Provincial Graduate Student Research Innovation Project (CX20240727). Conflict of Interest Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Reference [1] Hassoun PM. Pulmonary Arterial Hypertension. N Engl J Med 2021;385:2361–76. https://doi.org/10.1056/NEJMra2000348.[2] Dave J, Jagana V, Janostiak R, Bisserier M. 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Sci Rep 2017;7:4546. https://doi.org/10.1038/s41598-017-04874-4. AAV1.hSIN 3a SIN 3a Upregulate TET1 and DNMT1, reduce the methylation level in the BMPR2 promoter region, upregulate BMPR expression, alleviate cardiovascular remodeling, and decrease hemodynamic parameters such as RVSP and mPAP. [65] 5-Aza-dC DNMTs Inhibit the methylation level in the PTEN promoter region, upregulate PTEN protein expression, inhibit the proliferation and migration of PASMCs, and decrease mPAP and RVHI. [61] NEOU G6PD Inhibit G6PD activity, promote the expression of TET2, reduce the methylation level of target gene promoters, improve metabolic reprogramming in PASMCs, inhibit the proliferation of PASMCs. [115] Butyric Acid HDAC Ⅰ, HDAC Ⅱ Reduce RVSP and RVHI in a hypoxia-induced rat model of PH, and alleviate pulmonary vascular remodeling. [116] VPA、SAHA HDAC Ⅰ-Ⅳ Inhibit the proliferation of PASMCs and vascular fibroblasts, reduce inflammation, improve cardiopulmonary hemodynamics, and ameliorate pulmonary vascular remodeling. [78] MGCD0103、MS-275 HDAC Ⅰ3 Inhibit the proliferation of PASMCs, improve cardiopulmonary hemodynamics, attenuate right ventricular hypertrophy, and ameliorate pulmonary vascular remodeling. [77,117] Apicidin HDAC Regulate the gene expression profile of pro-oxidants and antioxidants, and inhibit the phenotypic switch of PASMCs. [118] MC1568 HDAC Restore MEF2 activity, inhibit the proliferation and migration of PAECs, and improve cardiopulmonary hemodynamics and ameliorate pulmonary vascular remodeling. [143] TubA HDAC6 Inhibit the proliferation and apoptosis resistance of PASMCs, and reverse the progression of PH. [144] Stac-3 SIRT Activate SIRT, correct the balance of histone acetylation/deacetylation, restore mitochondrial biosynthesis and oxidative phosphorylation mechanisms, inhibit the proliferation of PASMCs, and delay the progression of PH. [119] JQ1 BRD4 Inhibit the proliferation and anti-apoptotic phenotype of PASMCs, restore mitochondrial membrane potential, increase spare respiratory capacity, and reverse PH. [120] RVX208 BRD4 Inhibit the proliferation, inflammation, and apoptosis-resistant phenotype of PAECs and PASMCs, reverse vascular remodeling, and improve cardiopulmonary hemodynamics. [121] Apabetalone BRD2-4 Reduce pulmonary vascular resistance and improve hemodynamics. [122] Table 1 Existing “Epidrugs” for PH therapeutic potential. Figures Fig. 1 Metabolic reprogramming in PH. During the progression of PH, the metabolic pathways of vascular cells undergo alterations to satisfy the requirements for proliferation and biosynthesis inherent to their pathological state. The metabolic reprogramming of relevant cells in PH encompasses augmented uptake of glucose, fatty acids, and amino acids; a transition from oxidative phosphorylation to aerobic glycolysis; significant upregulation of the pentose phosphate pathway; inhibition of β-oxidation; lipid accumulation; enhanced polyamine biosynthesis; and elevated levels of glutamine and arginine metabolism. Fig. 2 DNA methylation regulates cellular metabolic reprogramming in PH. In PH, DNA methylation reprograms cellular metabolism. DNA methylation has the capacity to inhibit the expression of the ELK3 gene, resulting in an imbalance in mitochondrial fission and fusion, thereby suppressing fatty acid β-oxidation. Furthermore, it downregulates the expression of the SOD2 gene while concurrently activating HIF-1α, which inhibits oxidative phosphorylation and promotes aerobic glycolysis. Fig. 3 Histone methylation regulates cellular metabolic reprogramming in PH. This figure reveals how various histone methyltransferases and demethylases regulate metabolic reprogramming in PASMCs. EZH2 promotes glycolysis and glutamine metabolism in PASMCs through histone methylation, thereby maintaining the pathological phenotype of the cells. G9a catalyzes H3K9 methylation, which regulates cholesterol synthesis pathways and induces phenotypic changes in PASMCs. NSD2 mediates H3K36 demethylation, influencing cellular metabolic pathways through the regulation of trehalose. JMJD1C facilitates aerobic glycolysis by removing histone methylation, contributing to the development and progression of PH. Fig. 4 Histone acetylation regulates cellular metabolic reprogramming in PH. The figure elucidates the role of histone acetylation in modulating metabolic pathways across various vascular cell types in PH. In PASMCs, H3K27 acetylation enhances aerobic glycolysis, consequently driving cellular proliferation. In PAECs, decreased levels of H3K9 acetylation inhibit BOLA3 transcription, simultaneously activating glycine metabolism while compromising the integrity of iron-sulfur clusters and mitochondrial function, thereby upregulating glycolytic processes and inducing a proliferative and apoptosis-resistant phenotype. In fibroblasts, HDACs promote serine metabolism, the pentose phosphate pathway, and aerobic glycolysis, thereby facilitating cellular proliferation. Fig. 5 Noncoding RNA regulate cellular metabolic reprogramming in PH. The figure elucidates the mechanisms by which distinct ncRNAs reprogram the metabolic pathways of vascular cells, consequently inducing pathological phenotypes that facilitate the onset and progression of PH. Supplementary Material File (fig 1.tif) Download 20.40 MB File (fig 2.tif) Download 22.28 MB File (fig 3.tif) Download 21.81 MB File (fig 4.tif) Download 28.69 MB File (fig 5.tif) Download 33.77 MB File (table1.docx) Download 28.81 KB Information & Authors Information Version history V1 Version 1 26 February 2025 Peer review timeline Published Journal of Molecular Medicine Version of Record 3 Sep 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords epidrugs epigenetic modification metabolic reprogramming pulmonary hypertension Authors Affiliations Runxiu Zheng Hunan University of Chinese Medicine View all articles by this author Junlan Tan Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine View all articles by this author Xian-ya Cao Hunan University of Chinese Medicine View all articles by this author Shizhong Wang The First Hospital of Hunan University of Chinese Medicine View all articles by this author Qing Dai Hunan University of Chinese Medicine View all articles by this author Chao Zhang Hunan University of Chinese Medicine View all articles by this author Feiying Wang Hunan University of Chinese Medicine View all articles by this author Jian Yi Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine View all articles by this author Lan Song Hunan University of Chinese Medicine View all articles by this author Ai-guo Dai 0009-0003-3038-0358 [email protected] Hunan University of Chinese Medicine View all articles by this author Metrics & Citations Metrics Article Usage 222 views 127 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Runxiu Zheng, Junlan Tan, Xian-ya Cao, et al. Rewriting the Vascular Script: Epigenetic Modifiers as Scribes of Metabolic Reprogramming in Pulmonary Hypertension. Authorea . 26 February 2025. DOI: https://doi.org/10.22541/au.174055520.08538882/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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