Comorbidity of hypertension and lung cancer: interplay of genetics and environment

Abstract

Hypertension and lung cancer are two of the most prevalent chronic diseases worldwide, each contributing significantly to public health burdens. While both diseases have been extensively studied individually, their comorbidity remains an underexplored area of research. Recent studies suggest that genetic susceptibility plays a crucial role in the coexistence of these conditions, with overlapping genetic variants influencing both vascular homeostasis and tumorigenesis. The relationship between hypertension and lung cancer is complex, with shared risk factors and common pathogenic mechanisms, including inflammation, oxidative stress, and metabolic dysregulation. Environmental exposures—such as air pollution, tobacco smoke, and heavy metals—can trigger these genetic and epigenetic alterations, thereby increasing susceptibility to both conditions. Beyond genetic predisposition, epigenetic modifications significantly contribute to disease pathogenesis, including DNA methylation, histone modifications, and microRNA (miRNA) regulation. In hypertension, aberrant DNA methylation affects genes involved in vascular remodeling, such as At1b and Scnn1a, influencing blood pressure regulation. Similarly, in lung cancer, tumor suppressor genes such as p16, RASSF1A, and KCNK3 undergo methylation-induced silencing, promoting tumor progression. Histone modifications, particularly histone deacetylase (HDAC) activity, play a key role in both diseases, with HDAC inhibitors like valproic acid showing therapeutic potential in lowering blood pressure and inhibiting lung cancer cell proliferation. Understanding the shared genetic and epigenetic mechanisms between hypertension and lung cancer offers new opportunities for risk prediction, early intervention, and targeted therapies. Future research should focus on integrating genetic screening with environmental risk assessment to develop precision medicine strategies for individuals at high risk of both conditions.

Introduction

Hypertension is a major global health issue. According to epidemiological data, hypertension prevalence has doubled in the past 40 years, mainly as a result of an aging population. It is estimated that nearly 1.4 billion adults worldwide (over the age of 18, with 20% of women and 25% of men) have hypertension, with a significant portion of cases undiagnosed [1]. Hypertension is a major risk factor for cardiovascular diseases and the leading cause of mortality globally, resulting in approximately 7.6 million deaths annually [2]. Substantial evidence indicates that environmental exposure plays a crucial role in the development and progression of hypertension. For instance, exposure to occupational, social, and road traffic noise can impact hearing and is also associated with irritability or sleep disturbances [3]. Cancer remains the top cause of mortality worldwide. It is estimated that approximately 1 in 5 men and women are diagnosed with cancer, while around 1 in 9 men and 1 in 10 women die from it. In 2022, lung cancer was the most common type of cancer, with nearly 2.5 million new cases globally, accounting for 12.4% of all cancer cases. Lung cancer is also the leading cause of cancer-related deaths, with approximately 1.8 million deaths attributed to it (18.7%). The incidence and mortality rates of lung cancer continue to rise, particularly in regions with high smoking rates and severe air pollution [4]. Studies suggest that a substantial proportion of lung cancer cases can be attributed to environmental exposures. For example, the high incidence of lung cancer among Chinese women is believed to be associated with outdoor air pollution and household exposure to solid fuel combustion for heating and cooking [5]. Additionally, exposure to wildfires in the U.S. has been linked to poorer overall survival in patients with non-small cell lung cancer (NSCLC) who underwent surgical resection, highlighting the increased health risks faced by lung cancer patients in the context of wildfire exposure. This underscores the need to prioritize health risks related to wildfires in climate adaptation efforts [6].

Hypertension is known to have a strong genetic component, with heritability in the general population estimated at 25–60%. Extensive preclinical and clinical data suggest that elevated blood pressure and its associated cardiovascular risks are largely due to the interaction between genetic and environmental factors [7–11]. There is growing evidence that monogenic syndromes related to either hypertension or hypotension have substantial genetic contributions. Moreover, the identification rate of validated single nucleotide polymorphisms (SNPs) related to blood pressure in genome-wide association studies (GWAS) has increased exponentially. Over the past decade, GWAS and whole-exome sequencing have uncovered numerous potential blood pressure-related pathways, however consistent associations with hypertension remain uncommon or rare [12, 13]. These findings are not unique to hypertension; similar trends are observed in other complex chronic diseases, such as anemia and diabetes, as well as in lung cancer, which has reported similar results [14, 15]. While it is widely recognized that many lung cancer cases are triggered by smoking and other behavioral or environmental risk factors, there is also an acknowledged genetic risk element [16]. Genetic and environmental influences on various phenotypes and disease risks have cross-generational heritability. Extensive epidemiological and experimental evidence in model organisms and humans suggests that the effects of environmental exposure and genetic variation can be transmitted across multiple generations following exposure.

Cancer patients bear a substantial burden of cardiovascular disease, with hypertension being the most common cardiovascular condition among all cancer patients (10.8%), followed by diabetes (5.3%) and dyslipidemia (1.2%) [17]. Similarly, hypertension is one of the most common cardiovascular comorbidities among lung cancer patients [17, 18]. In lung cancer, hypertension is independently associated with mortality, with studies showing that patients with both lung cancer and hypertension have significantly poorer outcomes compared to those without comorbidities [19]. Additionally, in a cohort of 101,776 lung cancer cases, hypertension significantly increased mortality risk at 1-year (47.9%), 5-year (30.5%), and 10-year (28.2%) intervals compared to other non-pulmonary comorbidities [20]. Lung cancer is associated with high blood pressure levels, with every 10-mmHg increase in blood pressure increasing lung cancer risk by 10% [21]. There are many factors contributing to hypertension and lung cancer, and their incidence rates rise with age, which negatively impacts patients’ quality of life and places a heavy economic load on the global healthcare system. Experts have developed the concept of “tumor hypertension,” underscoring the close connection between cancer and hypertension [2]. Despite the fact that high blood pressure and lung cancer seem to belong to different domains, there is evidence that they may share some genetic and biological mechanisms. Consequently, exploring the genetic susceptibility of hypertension and lung cancer not only helps to reveal the common pathogenesis of these two diseases, yet al.so provides a scientific basis for the formulation of comprehensive prevention and treatment strategies as well as personalized medicine.

This review aims to comprehensively summarize and analyze existing research findings to explore the genetic susceptibility and potential shared mechanisms underlying hypertension and lung cancer. By systematically assessing studies on genetic polymorphisms, epigenetic modifications, and gene-environment interactions, we hope to provide valuable insights for researchers and clinicians in related fields. Additionally, we offer suggestions for future research directions to enhance our understanding of the intersection between these two disease states.

Potential relationship between hypertension and cancer

In cancer patients, hypertension remains an understudied but complex comorbidity, and current research shows inconsistent results in relation to hypertension and various cancer types. Although the causal relationship between cancer and hypertension is unclear, some studies have reported correlations between the two. Our understanding of the link between hypertension and cancer risk is evolving. For instance, hypertension has been observed to influence cancer risk, with studies reporting a statistically significant association between hypertension and an increased risk of breast cancer. In subgroup analyses, hypertension was positively correlated with breast cancer incidence in postmenopausal women [22]. Hypertension is also linked to an elevated overall risk of endometrial cancer [23]. Moreover, a meta-analysis of 86 prospective studies evaluating the association between hypertension and various cancer types indicated that hypertension may be associated with multiple types of cancer [24]. Researchers found that patients with a history of cancer are at a higher risk of hypertension, regardless of whether they receive active antitumor treatment. Numerous sensitivity analyses have confirmed a robust association between cancer and hypertension incidence. Patients with certain types of cancer are more likely to develop hypertension than those without cancer, with levels of risk varying according to cancer type [25]. Furthermore, there is a complex pattern to cancer risk among hypertensive patients. For example, a retrospective study found that, among men, diastolic blood pressure was associated with an increased risk of cancer, particularly in those smoking more than 10 cigarettes per day. Among men using antihypertensive drugs at baseline, functional stages of hypertension (Stage I: hypertension without end-organ damage; Stage II: hypertension with left ventricular hypertrophy; Stage III: hypertension with extracardiac organ damage) were significantly associated with increased cancer risk. In women who were not using antihypertensive drugs at baseline, diastolic blood pressure was linked to an increased risk of cancer [26].

Hypertension is a common side effect of many cancer therapies. Notably, certain anticancer treatments can cause a rapid rise in blood pressure, potentially worsening pre-existing cardiovascular conditions and, in severe cases, leading to acute hypertension-related complications [27]. Additionally, studies have shown that hypertension, whether treated or untreated, is modestly associated with increased cancer incidence and mortality [28]. Approximately 30% of cancer patients undergoing treatment also suffer from hypertension, and critical chemotherapy may be interrupted due to severe, newly onset, or worsening hypertension. For this patient group, timely diagnosis and optimal management of hypertension are crucial, as hypertension is a recognized risk factor for cardiotoxicity induced by chemotherapy. Without prompt treatment, it may alter cancer therapy, resulting in reduced or terminated doses of anticancer agents and potentially life-threatening end-organ damage [29]. Several classes of antineoplastic drugs, including vascular endothelial growth factor inhibitors, proteasome inhibitors, platinum derivatives, corticosteroids, and radiotherapy, are consistently associated with an increased risk of new-onset or uncontrolled hypertension in previously stabilized patients. Furthermore, hypertension is a primary risk factor for chemotherapy-induced cardiotoxicity, one of the most severe cardiovascular adverse effects of anticancer treatments. A growing body of evidence suggests that multiple antineoplastic agents accelerate the progression of hypertension [30].

The risk of cancer has also been linked to certain blood pressure medications. Calcium channel blockers (CCBs) are divided into dihydropyridine and non-dihydropyridine classes. Dihydropyridines include nifedipine, nicardipine, felodipine, and amlodipine, while non-dihydropyridines include diltiazem and verapamil. CCBs are widely used to control blood pressure and treat symptoms of angina [31]. For instance, diltiazem and verapamil have been shown to slow tumor growth in murine xenograft models of meningioma [32]. Amlodipine, a Ca²⁺ channel blocker commonly used for hypertension and angina, has been reported to inhibit the PI3K/Akt and Raf/MEK/ERK pathways via the epidermal growth factor receptor (EGFR) and regulate cell cycle-related proteins, such as cyclin D1, p-Rb, p27, and p21. Consequently, the combination of amlodipine and gefitinib achieves a synergistic effect in inhibiting cell proliferation by blocking the cell cycle. In xenograft models of A549 lung cancer, this combination effectively inhibits tumor growth compared to monotherapy, showing promising therapeutic potential [33].

Angiotensin receptor blockers (ARBs) are a class of drugs approved for the treatment of various common conditions, such as hypertension and heart failure [34, 35]. In 2003, Pfeffer et al. in a trial first observed that ARBs might increase in cancer risk [36]. A 2010 meta-analysis indicated a significantly increased risk of new cancer occurrence in patients randomized to ARB therapy. Among the specific cancers examined, only lung cancer incidence was significantly higher in patients treated with ARBs. While some mechanisms by which anticancer drugs induce hypertension have been identified, further preclinical and clinical studies are needed to elucidate the exact pathophysiology of hypertension associated with anticancer therapy and to optimize its management [37]. Other studies have reported that angiotensin II (Ang II) can accelerate cancer cell progression and metastasis. The renin-angiotensin system (RAS) plays an essential role in blood pressure regulation, and Ang II is a well-known pressor peptide associated with RAS. Ang II promotes hematogenous lung metastasis of melanoma cells by upregulating E-selectin in pulmonary vascular endothelial cells [38].

Family history and genetic susceptibility

The genetic susceptibility plays a critical role in the pathogenesis of both lung cancer and hypertension. Most individuals inherit susceptibility genes from their parents, although a few cases arise from new mutations not inherited from either parent. In an autosomal dominant inheritance pattern, if one parent carries a pathogenic cancer susceptibility gene alteration, their offspring have a 50% chance of inheriting the defective gene. Previous studies on familial risk of lung cancer have shown that individuals with a first-degree relative suffering from lung cancer, multiple family members suffering from lung cancer, or relatives with early-onset lung cancer have an increased risk of developing the disease themselves. Specifically, individuals with a family history of lung cancer among first-degree relatives (parents, siblings, or offspring) face approximately a 50% higher risk of lung cancer compared to those without such a history [39]. A recent meta-analysis also found that the risk of lung cancer is associated with having an affected father, mother, brother, or sister [40]. Moreover, another prospective study indicated that having a mother or maternal relatives with lung cancer is a risk factor for the disease [41]. In summary, family history serves as a straightforward indicator of genetic risk, influenced by shared and individual environmental exposures. Even after adjusting for smoking, the association between lung cancer and family history remains significant. In clinical practice, family history assessment is readily available and helps identify high-risk individuals. A positive family history of lung cancer should potentially be considered a variable when selecting individuals for lung cancer screening [42].

Similarly, family history is a valuable tool in identifying high-risk individuals for hypertension. Studies have shown that males with both parents diagnosed with hypertension exhibit elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) during both day and night [43]. Family studies also contribute to in validating genetic susceptibility models. By assessing the predictive power of polygenic models in high-risk individuals with a family history of hypertension, researchers can evaluate these models’ accuracy and practical application. For instance, a family history of cardiovascular disease can clinically help identify individuals at high risk of non-stroke cardiovascular events, irrespective of ethnicity, and those at increased risk of stroke among African Surinamese [44]. Moreover, predictive models have been developed for both SBP and DBP. The SBP model incorporates six environmental factors—age, BMI, waist circumference, weekly exercise frequency, and a parental history of hypertension (either one or both)—along with a single SNP (rs7305099). The DBP model includes six environmental factors (weight, alcohol intake, weekly exercise frequency, triglycerides, parental history of hypertension) and three SNPs (rs5193, rs7305099, rs3889728). The area under the curve (AUC) values for these models were 0.673 for SBP and 0.817 for DBP [45]. Then, specific findings from genetic polymorphism research have enhanced our understanding of how these genetic factors may regulate disease risk at the genetic level. Numerous polymorphic loci have been identified with significant associations with lung cancer and hypertension risk, offering a potential genetic basis for the comorbidity mechanisms of these two diseases. For example, a GWAS study in European populations identified that the 15q25.1 locus variation in the CHRNA5 gene (such as rs55781567) significantly increases lung cancer risk, but only in individuals who have smoked previously. Additionally, the LUAD GWAS in East Asian (EA) populations identified 12 novel variants, while a trans-ancestry meta-analysis between EA and European (EUR) populations discovered 4 new variants. In a dataset with ancestry-matched lung tissue, colocalization and analysis identified genes that may serve alveolar function. Notably, most variants identified in the EA GWAS had no evidence of association in EUR populations [46, 47].

Recent genetic studies have identified overlapping susceptibility loci that may underlie the comorbidity between hypertension and lung cancer. One such gene is MALAT1, a long non-coding RNA located on chromosome 11q13.1 initially discovered in NSCLC, which also plays a regulatory role in vascular biology. Previous studies have shown that MALAT1 plays a crucial regulatory role in lung cancer cell growth, metastasis, and invasion, and it is closely related to lung cancer prognosis [48, 49]. Concurrently, the rs664589 G allele of MALAT1 has been associated with a 1.33-fold increased risk of hypertension, particularly among individuals with obesity, male sex, or a history of smoking and alcohol use. Additionally, plasma MALAT1 levels are significantly lower in G allele carriers than in C allele carriers, suggesting that this polymorphism may influence hypertension development through lncRNA expression regulation [50]. These results suggesting its function spans both oncogenic and cardiovascular pathways. Another gene of particular interest is ALDH2, which encodes aldehyde dehydrogenase 2, a key enzyme involved in alcohol metabolism [51]. The rs671 polymorphism of ALDH2 has been linked to elevated lung cancer risk among drinkers and is also associated with increased carotid intima-media thickness and blood pressure in hypertensive patients. The ALDH2 polymorphism rs671 has been linked to elevated lung cancer risk among drinkers and is also associated with increased carotid intima-media thickness and blood pressure in hypertensive patients. Notably, the effects of this variant are modulated by alcohol consumption, highlighting a gene–environment interaction. Within specific drinking subgroups, rs671 has been associated with variations in systolic blood pressure and may modulate the tumor microenvironment (TME). Some studies have suggested that rs671 may influence the clinical response to PD-1/PD-L1 immunotherapy in thoracic malignancies, although its role as a predictive biomarker remains to be fully validated [52–54]. Another epigenetic regulator of interest is JMJD3 (also known as KDM6B), a histone H3K27 demethylase that plays crucial roles in both vascular and cancer biology. Genome-wide association studies have identified the rs62059712 T allele at the KDM6B locus as significantly associated with elevated SBP. Mechanistically, this variant disrupts SP1 transcription factor binding to the JMJD3 promoter, reducing its expression in vascular smooth muscle cells (SMCs). The resulting downregulation of JMJD3 leads to suppressed EDNRB expression and compensatory upregulation of EDNRA, promoting endothelin-mediated vasoconstriction, ERK pathway activation, and vascular remodeling—all key features of hypertension [55–57]. Beyond its role in vascular biology, JMJD3 also contributes to lung cancer progression through epigenetic reprogramming of metastasis-associated signaling pathways. Elevated JMJD3 expression has been consistently observed in human lung tumors and is particularly enriched in Ras-activated lung cancer cells. Mechanistic studies reveal that JMJD3 facilitates TGF-β/Smad signaling and epithelial–mesenchymal transition (EMT) by regulating syntenin, a scaffolding protein that enhances TGF-β signaling. Moreover, interferon-gamma (IFNγ) increases the expression of ZEB1 in a STAT1-JMJD3-dependent manner, thereby promoting the invasiveness of lung cancer cells [58–60]. In addition to its tumor-intrinsic functions, JMJD3 also modulates the tumor immune microenvironment. Recent studies using metastatic breast cancer models have demonstrated that cancer cell–derived exosomal miR-138-5p can be transferred to macrophages, where it suppresses JMJD3 expression, inhibits M1 polarization, and promotes M2-like immunosuppressive phenotypes. These reprogrammed macrophages contribute to enhanced lung metastasis, and circulating levels of exosomal miR-138-5p have been positively associated with disease progression in patients [61]. Although these findings were initially observed in breast cancer, the lung microenvironment appears to serve as a key site of immune modulation, suggesting broader implications for lung cancer as both a primary and metastatic target.

Overall, mounting evidence suggests that genetic and epigenetic susceptibility factors play a pivotal role in shaping the risk landscape of both lung cancer and hypertension. Family history serves as a practical proxy for inherited risk, while specific loci—such as MALAT1, ALDH2, and JMJD3—exemplify how shared molecular mechanisms may simultaneously influence oncogenic processes, vascular regulation, and immune responses. These findings not only underscore the biological overlap between the two conditions, but also support the hypothesis that lung cancer and hypertension may share common pathways.

Epigenetics

Epigenetic research involves heritable changes that affect gene expression without altering the DNA sequence, including DNA methylation, histone modifications, microRNA(miRNAs) and Long Non-Coding RNAs (lncRNAs) regulation. In recent years, epigenetics has been extensively studied in hypertension and lung cancer, uncovering the role these modifications play in disease onset and progression [62, 63].

DNA methylation

DNA methylation, a major epigenetic mechanism, involves the addition of methyl groups to DNA—typically at CpG islands—leading to transcriptional repression. Aberrant DNA methylation patterns are implicated in the onset and progression of both hypertension and lung cancer, particularly through the silencing of regulatory genes and modulation of cellular signaling pathways [64]. In hypertensive patients, certain gene loci frequently show abnormal DNA methylation [65, 66]. Genome-wide analyses have identified CpG sites significantly associated with both systolic and diastolic blood pressure, with some methylation changes shown to both predict and be influenced by blood pressure over time [67]. For example, methylation of the At1b gene, which encodes the angiotensin 1b receptor, contributes to salt-sensitive hypertension [68]. Importantly, non-CpG island regions and distal enhancers also participate in blood pressure regulation [69]. Complex interactions between DNA methylation and genetic variations have also been reported, specifically how methylation changes in non-coding regions affect hypertension onset and progression. The hypertension-related variant rs1275988, located in a cell-type-specific enhancer, aggravates hypertension by regulating local DNA methylation, Kcnk3 expression, and subsequent vascular remodeling. In animal models, the rs1275988C/C genotype, combined with a high-salt diet, exacerbates hypertension and induces pronounced vascular remodeling. Importantly, KCNK3 also plays a critical role in lung cancer. Prior studies demonstrated that KCNK3 is markedly downregulated in LUAD tissues and is associated with poor prognosis. Both in vivo and in vitro, KCNK3 overexpression substantially regulates carcinogenesis and glucose metabolism in LUAD. Mechanistic research revealed that KCNK3-mediated differential metabolites are primarily enriched in the AMPK signaling pathway [70]. These findings indicate that KCNK3 serves as a shared epigenetic mediator linking vascular dysfunction in hypertension and metabolic reprogramming in lung cancer. Moreover, classical methylation changes in lung cancer—such as silencing of tumor suppressors p16 and RASSF1A—further illustrate the importance of aberrant DNA methylation in tumorigenesis [71–75].Together, these observations support the notion that shared methylation-regulated pathways, exemplified by KCNK3, may underlie the molecular crosstalk between hypertension and lung cancer.

Histone modification

Histone modifications refer to structural changes in histones through chemical modifications, such as acetylation, methylation, and phosphorylation, which affect DNA packaging and gene expression. These modifications play a crucial role in gene regulation and cellular function. In hypertensive patients, abnormal histone acetylation and methylation are commonly observed, impacting vascular smooth muscle cell proliferation and function [76]. For example, in arterial hypertension, increased reactive oxygen species (ROS) and pro-inflammatory cytokines are regulated by histone deacetylase (HDAC) enzymes, which modulate the gene expression of these hypertension-promoting factors. HDAC inhibitors have been found to help regulate vascular tension and reduce blood pressure [77]. In spontaneously hypertensive rats, the well-studied HDAC inhibitor valproic acid has been shown to lower blood pressure, inflammatory cytokines, hypertrophy markers, and ROS levels [78]. Additionally, in a high-fat diet-induced hypertension mouse model, valproic acid was found to inhibit HDAC1, reducing angiotensin II and its receptor expression, thereby preventing hypertension progression [79]. Elevated HDAC expression and activity are also observed in certain cancers; for example, HDAC1-3 are overexpressed in ovarian cancer and HDAC1 and HDAC3 in lung cancer [80]. Research suggests that HDAC inhibitors could suppress tumor growth through anti-inflammatory and anti-proliferative effects. Valproic acid, for instance, has been reported to induce apoptosis in small cell lung cancer cell lines and enhance the effectiveness of cisplatin combined with etoposide—two standard first-line chemotherapy agents for small cell lung cancer. Valproic acid induces apoptosis in mitochondria and death receptors, and its anti-lung cancer effects can be enhanced by inhibiting cyclin-dependent kinases [81]. Histone modifications frequently observed in lung cancer cells include an increase in H3K27me3, a modification that promotes cancer cell growth and survival by suppressing tumor suppressor gene expression. Aberrant expression of histone-modifying enzymes, such as EZH2, is also associated with increased invasiveness and poor prognosis in lung cancer [82].

MiRNAs

MiRNAs are short, endogenous, non-coding RNAs that regulate gene expression at the post-transcriptional level by binding to the 3′ untranslated regions (UTRs) of their target mRNAs. Approximately half of miRNA genes undergo CpG promoter region hypermethylation, leading to miRNA silencing or downregulation [83, 84]. Substantial evidence supports this mode of action. For instance, CpG island hypermethylation-mediated silencing of miR-124a has been observed in various lung cancer cell lines, including H358, CALU3, A549, A427, H2126, and H209 [83]. Another study found that methylation-mediated downregulation of miR-200c is associated with increased invasive potential in NSCLC cell lines [85].

MiRNAs also play a significant role in hypertension. Hypertension-induced vascular remodeling is characterized by medial thickening, luminal narrowing, and extracellular matrix restructuring within the vascular wall. Vascular smooth muscle cells (VSMCs), as the main component of the vascular media, are crucial for maintaining vascular tone in response to hemodynamic and fluid changes, and play a pivotal role in vascular diseases like hypertension [86, 87]. Over the past decade, the role of miRNAs in VSMC development, phenotypic transformation, and vascular pathology has been widely studied. One of the most thoroughly investigated miRNA clusters in this regard is the miR-143/-145 family, which is enriched in VSMCs and transcriptionally regulated by serum response factor and myocardin [88, 89].

In addition to its impact on hypertension, the miR-143/-145 cluster is also critical in cancer. MiR-143/145 in the TME significantly promotes tumor growth by stimulating endothelial cell proliferation. In vivo, deletion of miR-143/145 results in the derepression of its target CAMK1D (an inhibitory kinase), whose overexpression impedes endothelial cell mitosis. Consequently, tumors in miR-143/145-deficient animals exhibit reduced angiogenesis, increased apoptosis, and restricted expansion due to limitations in their ability to engulf pulmonary vasculature [90]. Moreover, the interaction between the renin-angiotensin-aldosterone system (RAAS) and miRNAs also demonstrates a shared regulatory pattern in both lung cancer and hypertension. Certain genes within the RAAS, such as the vasopressin receptor (AVPR1A), interact with specific miRNA binding sites and are linked to the pathogenesis of hypertension. MiRNAs such as miR-526b and miR-578 regulate the expression of RAAS components, which not only exacerbate hypertension but may also influence tumor cell drug resistance and invasiveness, thereby further promoting the progression of lung cancer [91–94].

LncRNAs

LncRNAs are transcripts longer than 200 nucleotides that do not encode proteins but play essential roles in regulating gene expression at transcriptional, post-transcriptional, and epigenetic levels. Increasing evidence suggests that lncRNAs are critical contributors to both hypertension and lung cancer, serving as potential molecular bridges in their comorbidity [95–98].

Several lncRNAs have been implicated in both hypertension and lung cancer. H19, for instance, is upregulated in the decompensated right ventricle of PAH patients and is associated with right ventricular hypertrophy and fibrosis; it promotes vascular smooth muscle cell proliferation and inflammation in hypertension and is differentially expressed across patient subgroups. In lung cancer, H19 downregulation significantly reduces clonogenicity and anchorage-independent growth, and it acts as a critical downstream effector of c-Myc to promote tumorigenesis [99–101]. Similarly, GAS5 plays a dual protective role in both cardiovascular and cancer contexts. In hypertension, GAS5 is significantly downregulated in endothelial cells (ECs) and VSMCs, and its silencing exacerbates vascular remodeling, increases capillary leakage, and promotes endothelial dysfunction by modulating β-catenin signaling. In lung cancer, particularly NSCLC, reduced GAS5 expression is associated with advanced TNM stage and larger tumor volume. Mechanistically, GAS5 inhibits proliferation and promotes apoptosis through the regulation of E2F1, p21, and p53, and suppresses oncogenic pathways including EGFR, MAPK, and AKT. These findings underscore GAS5 and H19 as pivotal molecular nodes in both hypertension-induced vascular remodeling and lung cancer progression [99, 102–106].

Recent genome-wide association studies have also identified LINC00944 as a novel locus associated with blood pressure regulation. Some studies have found that LINC00944 may serve as a prognostic and immunological biomarker, linking tumor progression and immune features across NSCLC subtypes [107, 108]. Another notable lncRNA, MEG3, is downregulated in both hypertensive and lung cancer tissues and has been shown to modulate the p53 and Wnt signaling pathways. In NSCLC, MEG3 suppresses tumor proliferation and metastasis via the miR-21-5p/PTEN and MDM2/p53 axes, while in pulmonary hypertension, it promotes vascular remodeling by sponging miR-328-3p and upregulating IGF1R, highlighting its dual context-dependent roles in tumor suppression and vascular dysfunction [109–111].

These findings indicate that lncRNAs may represent a class of shared epigenetic regulators linking the pathogenesis of hypertension and lung cancer. Further research is warranted to explore their diagnostic and therapeutic potential in the context of disease comorbidity.

The role of gene-environment interactions in hypertension and lung cancer

Gene-environment interactions are key factors in understanding the pathogenesis of complex diseases such as hypertension and lung cancer (Fig. 1). Although inheritance genetics plays an important role in the development of these diseases, the influence of environmental factors and lifestyle cannot be ignored (Table 1). Not only can they directly affect the occurrence of disease, but they can also significantly increase an individual’s risk of disease through interaction with the genetic background.

Fig. 1.

Environmental and lifestyle risk factors contributing to hypertension and lung cancer. This figure illustrates the key environmental and lifestyle factors associated with the development of hypertension and lung cancer, including dietary patterns, occupational exposure, drinking water contamination, air pollution, smoking, alcohol consumption, heavy metal, and other exposures. These factors are depicted with corresponding icons and linked to their impact on the human respiratory and cardiovascular systems, highlighting the interplay between genetic susceptibility and environmental triggers

Table 1.

Influence of exposures on hypertension and lung cancer

Environmental factors/lifestyle	Primary sources	Impact on hypertension	Impact on lung cancer	References
Air pollution	Industrial emissions, vehicle exhaust, PM2.5	PM2.5 induces ROS generation, reduces NO levels, leading to vascular dysfunction.	PM2.5 particles carry carcinogens such as polycyclic aromatic hydrocarbons, causing DNA damage and mutation accumulation.	[282–290]
		Long-term exposure can activate chronic inflammatory pathways (such as IL-6, TNF-α).	Chronic lung inflammation increases the risk of tumor angiogenesis and invasion.
Smoking	Tobacco products	Nicotine activates the sympathetic nervous system, causing vasoconstriction and inflammatory responses.	Carcinogens like benzo[α] pyrene in tobacco directly induce DNA mutations and interfere with DNA repair functions, promoting cancer development.	[291–296]
		Tobacco chemicals promote vascular hardening and arterial inflammation, exacerbating the hypertension process.	Inhibits immune system function, enhancing tumor escape ability.
Occupational exposure	Heavy metals (lead, cadmium), benzene compounds	Heavy metals activate vascular inflammatory responses through ROS generation and NF-κB pathway activation.	Benzene compounds form adducts with DNA, leading to gene mutations.	[297–303]
		Cadmium can induce apoptosis of vascular endothelial cells, leading to endothelial dysfunction.	Asbestos fibers stimulate chronic pulmonary inflammation, accelerating cancer development.
Dietary patterns	High-salt diet, saturated fat intake	A high-salt diet activates the RAAS system, leading to increased blood volume and elevated vascular tone.	A high-fat diet promotes tumor development by regulating the tumor microenvironment metabolism and pro-inflammatory responses, supporting lipid metabolic remodeling and signal molecule release.	[304–308]
		A high-fat diet supports pro-inflammatory and pathogenic environments, such as promoting the release of trimethylamine N-oxide, thereby accelerating the development of atherosclerosis.
Drinking water contamination	Heavy metals (arsenic, lead), organic pollutants	Arsenic contamination is associated with increased blood pressure, possibly through ROS generation leading to vascular dysfunction.	Arsenic increases cancer risk by inducing DNA damage and interfering with DNA repair functions.	[300, 309–313]
		Arsenic in drinking water causes vascular endothelial dysfunction, manifesting as imbalances in vasodilation and vasoconstriction.	Organic pollutants may be associated with lung cancer through epigenetic regulation.
Microplastics	Plastic degradation in the natural environment	Microplastics can enter the human cardiovascular system, triggering inflammation, oxidative stress, and other reactions, thereby promoting the development of cardiovascular diseases such as atherosclerosis and myocardial injury.	By physically penetrating cells and chemically inducing reactive oxygen species, microplastics cause cellular dysfunction and genomic instability, thereby promoting lung cancer progression.	[314–325]

Diet and drinking habits

Dietary habits play a crucial role in the development of hypertension. The intake of high amounts of salt is strongly associated with hypertension, as excessive sodium levels in the body resulting from increased dietary intake or reduced urinary excretion are well-established risks for hypertension. A cross-sectional studies show that populations with higher sodium intake tend to have elevated average blood pressure levels and a higher prevalence of hypertension [112]. In a prospective cohort study, high sodium intake was shown to predict mortality and coronary heart disease risk independently of other cardiovascular risk factors, including blood pressure, providing direct evidence of the harmful effects of high salt intake in adults [113]. Additionally, in the absence of exogenous antioxidants, cancer cells maintain redox homeostasis by expressing endogenous antioxidants. Antioxidants in the diet can reduce reactive oxygen species (ROS) and DNA damage in tumors, suppressing the expression of p53, a tumor suppressor typically activated by DNA damage [113]. For instance, supplementation with antioxidants like N-acetylcysteine (NAC) and vitamin E in the diet can accelerate the progression of primary lung tumors in Kras2 LSL/+ (K) mice [114]. Inorganic arsenic in water and food is a key toxic substance for risk assessment and exposure mitigation. Chronic exposure to arsenic can affect multiple organ systems, leading to various cancers, cardiovascular diseases, and respiratory conditions [115, 116]. Among study participants, a statistically significant association was found between arsenic exposure through drinking water and hypertension, with cumulative lifetime arsenic exposure of 2,188–7,025 µg/L-years and > 7,025 µg/L-years yielding odds ratios for hypertension of 1.12 (95% CI: 0.84, 1.49) and 1.60 (95% CI: 1.20, 2.13), respectively [117]. A 13-year study in southwestern Taiwan also found that diastolic blood pressure increased with higher arsenic intake from drinking water [118]. Arsenic has a documented impact on both hypertension and lung cancer. Between 1950 and 1969, studies found that white men and women living in counties with copper, lead, or zinc smelting and refining industries had a significantly higher average lung cancer mortality rate. Later investigations suggested that inorganic arsenic emissions from these industries likely played a major role [119]. Numerous statistical studies and experiments have since confirmed this association, establishing lung cancer as one of the most fatal cancer types linked to arsenic exposure [120, 121]. Furthermore, among both smokers and nonsmokers, arsenic-induced lung cancers predominantly manifest as squamous cell carcinoma (SqCC) and small cell carcinoma (SCC) [122]. Chronic arsenic exposure may also cause epigenetic changes, such as the arsenic-induced depletion of S-adenosylmethionine (SAM), which can alter CpG methylation in gene promoters, including p53 [123–125]. It has been reported that arsenic exposure modifies histone methylation patterns, particularly in H3K4, H3K9, and H3K27, in both malignant and non-malignant lung cell lines. These changes lead to reduced gene expression through alterations in histone acetylation and DNA methylation [126, 127].

Alcohol

Drinking alcohol is a significant environmental factor impacting the development of various chronic diseases, including hypertension and cancer. A growing body of research shows that long-term excessive alcohol consumption not only contributes to the onset of hypertension but also is associated with increased risks of several cancers. Excessive alcohol intake is a notable trigger for hypertension, showing a dose-dependent relationship with elevated blood pressure and the prevalence of hypertension [128]. Studies have found that prolonged alcohol consumption activates the renin-angiotensin system, raising blood pressure and causing vascular damage. Alcohol elevates blood pressure by influencing sodium and water reabsorption and activating the sympathetic nervous system. Moreover, gene-environment interactions may play a critical role in the process by which alcohol induces hypertension [129, 130]. For instance, genetic polymorphisms in genes such as ADH1B and SLC39A8 are closely related to drinking habits and blood pressure regulation in hypertensive individuals. People with these specific genetic variants are more susceptible to blood pressure elevation after alcohol consumption [131]. Additionally, a cohort study of 371,463 individuals provided genetic evidence that varying alcohol intake levels are linked to a persistent, nonlinear increase in the risk of hypertension and coronary artery disease. Moderate alcohol consumption led to a slight increase in risk, while higher intake resulted in a sharp, exponential rise in risk [132]. Even without hypertension, daily alcohol intake can raise blood pressure. A meta-analysis of seven cohort studies involving nearly 20,000 healthy participants from Japan, Korea, and the United States showed that daily alcohol consumption was associated with elevated systolic blood pressure in non-hypertensive individuals. Those who drank about 12 g of alcohol daily (equivalent to less than one beer or five ounces of wine) had systolic blood pressure readings 1.25 mmHg higher than non-drinkers. A dose-response relationship was also observed: a daily intake of 48 g of alcohol resulted in a systolic blood pressure increase of 4.90 mmHg [133]. The link between alcohol consumption and lung cancer is more complex. Although alcohol itself is not a primary cause of lung cancer, the risk of lung cancer significantly increases when combined with smoking. Acetaldehyde, a carcinogenic byproduct of alcohol metabolism, can damage DNA and may exacerbate the carcinogenic effects of tobacco, thereby contributing to the development of lung cancer [134]. In lung cancer, specific genetic polymorphisms, such as the Arg48His polymorphism in the ADH1B gene, are associated with an increased risk of alcohol-related lung cancer. Studies have shown that individuals carrying the Arg48His variant have a more than threefold increased risk of lung cancer when drinking 10 to 29.9 g of alcohol daily [135]. Furthermore, alcohol consumption may alter the TME, enhancing the growth and spread of cancer cells. Interactions between alcohol consumption and genetic background play a critical role in the development of both hypertension and lung cancer. Specifically, polymorphisms in ethanol-metabolizing genes like ADH1B and ALDH2 are closely linked to oxidative stress, DNA damage, and inflammatory responses induced by alcohol consumption. Alcohol increases free radical production, disrupts the body’s antioxidant defenses, induces chronic inflammation, and affects gene expression regulation, ultimately heightening an individual’s disease susceptibility [53, 54, 134].

Smoking

Smoking is one of the major causative factors in multiple diseases, particularly in the development of lung cancer and cardiovascular disease, where it plays a crucial role. Long-term smoking not only elevates the risk of lung cancer but is also closely associated with the incidence of hypertension. Among the more than 60 identified carcinogens in cigarette smoke, at least 20 are credible lung cancer carcinogens. Additionally, numerous pro-inflammatory changes have been observed in the lungs of smokers, with inflammation closely linked to tumor promotion and the activation of factors like NFκB [136–138]. In a case-control study involving smokers with normal lung function, COPD, and lung cancer (COPD subtype), it was found that the GG genotype of the rs1489759 HHIP SNP and the CC genotype of the rs2202507 GYPA SNP exhibited a “protective” effect against both COPD (OR 0.59, p = 0.006 for HHIP and OR = 0.65, p = 0.006 for GYPA) and lung cancer (OR = 0.70, p = 0.05 for HHIP and OR = 0.70, p = 0.02 for GYPA) [139]. Compared to non-smoking-related lung cancer, rare sensitizing and non-sensitizing EGFR mutations are more likely to occur in smoking-related lung cancer cases; however, approximately 60% of rare EGFR exon 20 insertion cases involve patients who have never smoked, with most being female (similar to patients with classical sensitizing EGFR mutations) [140–142]. A 2013 GWAS meta-analysis involving two independent cohorts identified SNPs associated with overall survival in never-smoking European NSCLC individuals. Among the top 25 SNPs, six showed genotype-expression associations in expression quantitative trait locus analysis. These variants were neither in genes previously linked to lung cancer risk in non-smokers nor in those associated with OS in smoking-related lung cancer patients. In the initial consistency meta-analysis, three of these variants reached genome-wide significance (rs7976914, rs4237904, and rs4970833) [143, 144]. Likewise, smoking can induce hypertension-related changes. Blood pressure is a classic complex hereditary trait with heritability estimated at 30–50%. The gene encoding the G(s) protein α-subunit (GNAS1) is a candidate genetic determinant of hypertension. A Japanese study involving 2,000 patients showed a significant interaction between GNAS1 polymorphisms and smoking in the pathogenesis of hypertension (p = 0.0005). This interaction was observed in non-heavy smokers, where a significant association was found between the gene polymorphism and hypertension (odds ratio = 1.52, 95% confidence interval 1.16 to 2.00, p = 0.0028). Among non-heavy smokers, a significant interaction between this gene polymorphism and aging was also noted in the pathogenesis of hypertension [145]. Furthermore, studies have reported a major quantitative trait locus for systolic blood pressure on chromosome 15q in non-smokers, indicating loci that influence blood pressure via gene-smoking interactions [146].

Air pollution

Air pollution is recognized as one of the leading global threats to human health, playing a crucial role in the development of both hypertension and lung cancer. Increasing evidence suggests that long-term exposure to air pollutants, such as nitrogen dioxide (NO₂) and ozone, significantly raises the risk of cardiovascular and respiratory diseases [147–150]. Epidemiological data and findings from mouse and human cell models indicate that particulate matter with an aerodynamic diameter smaller than 2.5 μm (PM2.5) promotes lung cancer by stimulating the growth of lung cells with pre-existing carcinogenic mutations. Studies have shown that PM2.5 exposure activates APOBEC3B, leading to gene mutations associated with the APOBEC mutation signature. This mechanism has been validated among lung cancer patients from four distinct geographic regions, suggesting that PM2.5 exposure may trigger lung cancer-related gene mutations through APOBEC3B and DDR (DNA damage response) pathway activation [151]. Research has also linked PM2.5 levels to 32,957 cases of EGFR-driven lung cancer across four countries. The study found that exposure to air pollutants triggers macrophage infiltration into mouse lungs, leading to the release of interleukin-1β, which promotes tumor growth [152]. A study on data from 400,000 individuals across the UK and Asian countries examined the association between lung cancer, particularly EGFR-mutant lung cancer common among non-smokers, and PM2.5 concentrations below 2.5 μm. The findings indicated a positive correlation between higher PM2.5 levels and the incidence of EGFR-mutated lung cancer and other cancers [153]. Indoor air pollution also contributes to lung cancer risk. For instance, primary human airway epithelial cells exposed to smoke extracts from traditional stoves (TCS), improved stoves (ICS), and liquefied petroleum gas (LPG) stoves showed changes in gene expression, DNA methylation, and hydroxymethylation after sulfonic acid conversion. TCS extracts alone caused alterations in 52 genes involved in oxidative stress pathways, while exposure to TCS, ICS, and LPG smoke extracts resulted in significant changes in DNA methylation and hydroxymethylation [154].

Similarly, air pollution is known to impact hypertension. Prior studies have shown that air pollution may be a risk factor for hypertension, as long-term environmental air pollution exposure has been associated with increased cardiovascular mortality. Hypertension is a critical risk factor for cardiovascular disease. Recent findings indicate that individuals exposed to PM2.5 experience increased arterial blood pressure within hours to days after exposure [155]. Another study reported a positive association between hypertension incidence and long-term exposure to PM2.5 and nitrogen oxides [156]. Short-term exposure to sulfur dioxide (SO₂), PM2.5, and PM10 showed a significant correlation with hypertension. Long-term exposure to NO₂ and PM10 was also significantly associated with hypertension. Exposure to other environmental air pollutants, including short-term exposure to NO₂, ozone, and carbon monoxide, as well as long-term exposure to NO_x, PM2.5, and SO₂, showed positive associations with hypertension, though without statistical significance [157]. Furthermore, epigenetic age acceleration (EAA), an epigenetic biomarker of aging, has been linked to indoor air pollution from coal combustion and associated pulmonary arterial hypertension, particularly 5-methylcytosine, which correlates with the mortality biomarker Grim Age EAA [158].

Radon

Radon is a naturally occurring radioactive gas released from the decay of uranium in rocks and soil, and it can infiltrate indoor environments through building foundations, accumulating especially in poorly ventilated residential spaces. It has long been recognized as the second leading cause of lung cancer globally after tobacco smoking, accounting for an estimated 10–20% of lung cancer cases and 3–20% of lung cancer-related deaths. The risk appears particularly pronounced among never-smokers, with dose–response studies confirming that both the concentration and duration of radon exposure are critical. Inhabitants of homes with indoor radon levels exceeding 300 Bq/m³ are at significantly increased risk, and long-term exposure beyond 40 years further compounds this risk. Recent studies have also indicated sex-specific effects, with males potentially being more susceptible than females [159–163].

Beyond its well-established pulmonary carcinogenicity, growing evidence implicates radon exposure in cardiovascular pathophysiology. A large-scale cohort study from Massachusetts reported a 15% increased risk of hypertensive disorders of pregnancy (HDP) associated with an interquartile-range increase in residential radon levels, independent of traditional risk factors such as age, socioeconomic status, and PM2.5 exposure. The effect was even more pronounced (up to 38%) in women under 20 years of age. This suggests that radon may impair vascular health by promoting endothelial dysfunction, oxidative stress, and systemic inflammation—mechanisms also central to hypertension development [164].

Mechanistically, radon and its radioactive progeny emit alpha particles that can cause direct DNA damage, genomic instability, and persistent low-grade inflammation in lung tissues. These processes not only facilitate oncogenesis but may also contribute to vascular remodeling and stiffness—hallmarks of hypertensive pathology. Moreover, radon exposure has been linked to disrupted redox balance and impaired nitric oxide (NO) signaling, both of which are pivotal in maintaining vascular tone and endothelial function. These shared molecular alterations highlight radon exposure as a potentially modifiable environmental risk factor in the comorbidity of lung cancer and hypertension [165–167]. Given its ubiquitous presence in many regions and its often underestimated health impact, radon warrants further investigation as a dual risk factor in pulmonary and cardiovascular pathology.

Asbestos

Asbestos, a group of naturally occurring fibrous minerals, has long been recognized as a potent environmental carcinogen, particularly associated with lung cancer, mesothelioma, and asbestosis. Epidemiological data suggest that the incidence of asbestos-related lung cancer (ARLC) is approximately six times higher than that of mesothelioma, and all six commercially used types of asbestos fibers are implicated in carcinogenesis. Both occupational and environmental asbestos exposure significantly increase lung cancer risk, even in non-smokers, and there appears to be no safe threshold of exposure. In some regions, particularly those with naturally contaminated soil or historical industrial activity, environmental asbestos exposure contributes to an elevated incidence of lung cancer, often diagnosed at younger ages and in both sexes [168–172].

In addition to its established role in cancer, asbestos exposure is increasingly linked to cardiovascular outcomes, particularly pulmonary hypertension. Asbestosis—a fibrotic lung disease resulting from chronic inhalation of asbestos fibers—impairs gas exchange, increases pulmonary vascular resistance, and can lead to right heart strain and heart failure. A meta-analysis by Yi Rong et al. further confirmed that asbestos exposure is associated with a statistically significant increase in cardiovascular mortality among exposed workers (pooled SMR = 1.11, 95% CI: 1.01–1.22) [173]. Moreover, studies have reported higher rates of ischemic heart disease and cerebrovascular mortality in asbestos-exposed populations [174]. Mechanistically, Chronic inhalation of asbestos fibers induces persistent pulmonary inflammation and fibrosis, which not only impairs gas exchange but also contributes to pulmonary vascular remodeling, ultimately leading to pulmonary hypertension. The sustained elevation of pulmonary arterial pressure increases right ventricular afterload, thereby predisposing individuals to right-sided heart failure [175–177].

Recent Korean cohort studies reinforce this health burden, showing that patients with occupational asbestos exposure—whether diagnosed with mesothelioma or ARLC—have shorter survival times and lower 3- and 5-year survival rates compared to those with environmental exposure. Furthermore, longer exposure duration and closer proximity to asbestos sources were significantly associated with worse prognosis [178]. Taken together, these findings underscore asbestos as a shared environmental risk factor in the comorbidity of lung cancer and hypertension.

Common biological pathways

Lung cancer and hypertension, despite being distinct diseases, share several underlying biological mechanisms (Fig. 2).

Fig. 2.

The common biological mechanisms between hypertension and lung cancer. This figure highlights the shared biological mechanisms underlying hypertension and lung cancer, focusing on five core processes: oxidative stress, metabolic dysregulation, immune dysfunction, inflammation, and vascular endothelial dysfunction. Oxidative stress, driven by the accumulation of reactive ROS, reduces NO bioavailability, induces DNA damage, and triggers the release of pro-inflammatory cytokines, leading to endothelial dysfunction, vascular remodeling, and TME alterations. Metabolic dysregulation manifests in hypertension as mitochondrial dysfunction and lipid metabolism abnormalities, contributing to insulin resistance and vascular damage, while in lung cancer, metabolic reprogramming, including the Warburg effect and lipid metabolism alterations, supports tumor growth and invasion. Chronic inflammation is a hallmark of both diseases, where cytokines such as IL-6 and TNF-α drive vascular inflammation and remodeling in hypertension and induce DNA damage, promote angiogenesis, and facilitate immune escape in lung cancer. Immune dysfunction, characterized by immune cell infiltration and cytokine release, exacerbates vascular damage in hypertension, whereas in lung cancer, immune escape mechanisms such as PD-L1 upregulation and immunosuppressive microenvironments enable tumor progression. Finally, vascular endothelial dysfunction is central to both diseases, presenting as vascular remodeling and endothelial gap widening in hypertension and as abnormal angiogenesis and endothelial barrier breakdown in lung cancer, facilitating tumor growth and metastasis

The vascular endothelial dysfunction

Endothelial cells line the inner layer of blood vessels and play critical roles in regulating vascular tone, maintaining blood flow, and providing anticoagulant properties. Under normal conditions, endothelial cells secrete various vasoactive substances, such as NO and prostaglandins, which facilitate vasodilation to maintain balanced blood pressure. However, in hypertensive patients, endothelial function is often compromised, leading to what is known as “endothelial dysfunction.” Typically, these cells modulate blood vessel dilation and contraction by releasing factors like NO, prostaglandins, and endothelin, thereby stabilizing blood pressure. During endothelial dysfunction, structural and functional abnormalities arise in the endothelial cells, impairing their ability to regulate vasodilation, thrombosis, and vascular wall repair. This dysfunction manifests as reduced vascular response to dilators (particularly to NO and prostacyclin), heightened pro-inflammatory responses leading to vascular wall inflammation, increased oxidative stress contributing to vascular damage, and pathological changes. For instance, NO, a critical factor for vasodilation, is synthesized by endothelial NO synthase (eNOS) within endothelial cells [179–183]. In hypertensive conditions, NO production is reduced, or its bioavailability decreases, resulting in enhanced vasoconstriction. Oxidative stress plays a key role in lowering NO bioavailability. In hypertensive individuals, elevated ROS levels combine with NO to form harmful peroxynitrite, effectively lowering active NO levels [184]. Oxidative stress, marked by an excess of ROS relative to antioxidant systems, is a key pathological mechanism in hypertension. ROS not only directly damage endothelial cells but also inhibit eNOS activity, further reducing NO production and aggravating vasoconstriction. The interplay between oxidative stress and diminished NO forms a vicious cycle, worsening hypertension [182, 185]. Inflammation and oxidative stress from endothelial dysfunction stimulate vascular smooth muscle cell proliferation, leading to vascular wall thickening and luminal narrowing. This vascular remodeling decreases elasticity, heightening peripheral resistance and blood pressure [186, 187].

In cancers such as lung cancer, endothelial dysfunction can promote tumor growth and metastasis through various mechanisms [188–190]. Lung cancer cells secrete multiple pro-angiogenic factors like vascular endothelial growth factor (VEGF), which stimulate endothelial cell proliferation and new blood vessel formation, supplying the tumor with blood and essential nutrients [191, 192]. Under conditions of endothelial dysfunction, dysregulated angiogenesis creates an abnormal vascular network [193]. Unlike normal vessels, tumor-associated blood vessels tend to be fragile and highly permeable, facilitating cancer cell dissemination to distant organs through the bloodstream [194]. VEGF overexpression is especially critical, as tumor cells use it to drive angiogenesis around them, securing essential oxygen and nutrients for growth and metastasis [195]. Endothelial dysfunction increases vascular wall permeability, facilitating the infiltration of inflammatory cells such as macrophages and lymphocytes into the TME. These cells release various pro-inflammatory factors, which further drive cancer cell proliferation and metastasis [196–198]. Endothelial dysfunction is not only a key pathological feature of hypertension but also an early warning sign of cardiovascular disease. Additionally, it plays a significant role in the progression of lung cancer. Many anti-angiogenic therapies, such as VEGF inhibitors, suppress tumor growth and metastasis by blocking angiogenesis and repairing abnormal endothelial cells [199, 200]. In conclusion, treatments that improve endothelial function may help reduce the combined risk in patients with both hypertension and lung cancer.

Inflammation

Inflammation is a protective response to injury or infection, yet chronic systemic inflammation plays a central role in the pathogenesis of hypertension and cancer [201, 202]. Individuals with inflammation-mediated diseases are more susceptible to hypertension. For example, compared to individuals without these inflammatory conditions, patients with psoriatic arthritis have a 90% higher risk of hypertension [203], those with rheumatoid arthritis have a 50% higher risk [204], and individuals with periodontitis have a 22% increased risk of hypertension [205]. Even in patients without classic inflammation-mediated diseases, inflammatory dysregulation has been observed in primary hypertension. As blood pressure increases, plasma levels of C-reactive protein (CRP) [206, 207]and cytokines (particularly IL-6, tumor necrosis factor (TNF) [208, 209], and IL-1β, IL-18, and CC chemokine ligand 2 (CCL2) also elevate [210–213]. Various cytokines can also impact vascular function and structure, as well as renal sodium transport, ultimately resulting in increased systemic vascular resistance, elevated blood pressure, and sodium and volume retention [214, 215]. The lipopolysaccharide (LPS) endotoxin produced by gram-negative bacteria can trigger a strong immune response, and intraperitoneal injection of LPS in rodents serves as a classic model of systemic inflammation. In rats, LPS-induced elevations in plasma CRP, tumor necrosis factor-alpha (TNF-α), and IL-1β levels are associated with increases in blood pressure. In LPS-treated rats, cyclooxygenase-2 inhibition can prevent blood pressure elevation, suggesting that LPS-induced inflammation contributes to the hypertensive effect [216]. While GWAS studies have identified SNPs in gene loci that play roles in classical hypertension mechanisms (such as vasoconstriction, sodium reabsorption, and sympathetic nervous system activity), the identified gene loci also relate to inflammation and immunity. A recent meta-analysis revealed that among 97 genes from various GWAS containing SNPs associated with hypertension, 81 had direct or indirect roles in inflammation and/or immunity [217].

Chronic inflammatory responses also contribute to tumor promotion [218]. Tumor-associated inflammation involves complex interactions between epithelial and stromal cells, which can sometimes result in epigenetic changes that drive malignancy or even initiate tumorigenesis. Generally, chronic inflammation leads to the production of growth factors that support the development of nascent tumors, making them resemble “wounds that do not heal” [218, 219]. Cancer biology is shifting from focusing solely on cancer cells to a broader view. This new perspective places cancer cells within a network of stromal cells, including fibroblasts, vascular cells, and immune cells, all of which together form the TME. Inflammation, whether occurring within the context of chronic inflammatory disease or tumor-induced inflammation, significantly influences TME composition, particularly the plasticity of tumor and stromal cells [218]. A hallmark of cancer is the loss of cell-intrinsic tumor suppressive functions. One of the most frequently mutated tumor suppressors is Tp53, which encodes the p53 protein. The p53 protein has various functions in regulating cellular homeostasis, one of which includes transcriptional antagonism of NF-κB, a key positive regulator of inflammation [220, 221]. Due to the persistent NF-κB activation signaling present within the TME and even normal tissues, the loss of functional p53 leads to increased NF-κB-dependent inflammatory gene expression. In cancer, this inflammatory profile promotes tumor progression and metastasis [221–223].

Immune dysregulation

For decades, immune cells and cytokines have been associated with human hypertension, but recent advances in immunological tools and animal models have allowed detailed examination of their roles in various experimental models. New data from both human and rodent models suggest that immune cells are not passive bystanders but play an essential role in hypertension and cancer [221, 224–227]. Immune responses can occur in the intima, media, and adventitia of blood vessels. The endothelium and microvascular endothelial cells in these layers are critical for the recruitment and activation of leukocytes, which commonly contribute to the pathophysiological processes of hypertension and target organ damage. Current research indicates that both innate and adaptive immunity are involved in the pathogenesis of hypertension [228–230]. Studies have shown that mice with mutations in the colony-stimulating factor 1 gene, which causes monocyte/macrophage dysfunction, have reduced blood pressure elevation and vascular injury when exposed to Ang II or DOCA (deoxycorticosterone acetate) and salt [231, 232]. Animal studies have also demonstrated that Rag1 knockout mice, which lack mature T and B cells, show reduced Ang II-induced salt-sensitive hypertension [229, 233]. A study on the effect of Ang II on humanized mouse models found that Ang II treatment increased total CD3 + and CD4 + T helper cells, as well as CD45RO + memory T cells in the kidneys. This effect was eliminated by preventing hypertension with hydrochlorothiazide and hydralazine [234]. Numerous immune cells infiltrate the vascular wall, releasing cytokines like TNF-α, IL-6, and interferon-gamma (IFN-γ), which damage endothelial cells, promote vascular remodeling, and increase vascular resistance, ultimately leading to hypertension [225, 226]. Furthermore, genetic polymorphisms associated with immune response have been found to influence susceptibility to hypertension. A Mendelian randomization study reported a consistent, positive, and potentially causal association between lymphocyte count and systolic and diastolic blood pressure [235].

The development and progression of lung cancer are closely linked to immune escape. Immune cells in the TME, such as macrophages and T cells, can be reprogrammed by cancer cells to support tumor growth rather than suppress it. Cancer cells evade antitumor immune responses by secreting immunosuppressive factors like transforming growth factor-beta (TGF-β) and PD-L1, allowing the tumor to proliferate and metastasize [236, 237]. T lymphocytes with deletion variants exhibit lower caspase-8 activity and experience activation-induced cell death when stimulated by cancer cell antigens. A case-control study involving 4,995 cancer patients and 4,972 controls from a Chinese population found that a variant in the Caspase-8 gene was associated with reduced susceptibility to several cancers, including lung, esophageal, gastric, colorectal, cervical, and breast cancers. The effect was dose-dependent, with the degree of susceptibility linked to the number of risk alleles [238]. Studies have shown that the rs822336 SNP in the PD-L1 promoter/enhancer region affects PD-L1 expression by competing for binding sites with the transcription factors C/EBPβ (CCAAT-enhancer-binding protein beta) and NFIC (nuclear factor I C). This interaction helps predict how advanced NSCLC patients will respond to anti-PD-1/PD-L1 immunotherapy, offering a new predictive biomarker [239]. These findings suggest that genetic variants modulating immune function may contribute to susceptibility to both cancer and hypertension.

Oxidative stress

Oxidative stress plays a critical role in hypertension due to the fundamental roles of ROS and redox signaling in molecular, cellular, and systemic processes that contribute to endothelial injury, vascular dysfunction, cardiovascular remodeling, renal impairment, sympathetic nervous system excitation, immune cell activation, and systemic inflammation—key factors in the pathophysiology of hypertension [240, 241]. ROS are among the many molecular contributors to hypertension progression. ROS, small molecules derived from molecular oxygen through redox reactions or electron excitation, include free radicals such as superoxide anion and non-radicals such as hydrogen peroxide. Due to their highly reactive nature, ROS promote the oxidation of proteins, DNA, and lipids, ultimately disrupting cellular function and viability [242]. In fact, studies have demonstrated that oxidative stress plays a causal role in the pathogenesis of hypertension across various animal models [243]. Evidence from experimental models indicates that oxidative stress and hypertension have a causal relationship [244, 245]. ROS are closely associated with hypertension’s major pathogenic features, including endothelial dysfunction, vascular hyperreactivity, vascular injury, arterial remodeling, renal impairment, sympathetic nervous system activation, inflammation, and immune cell activation [244, 246]. Moreover, treatment with antioxidants and ROS scavengers can sustainably reduce blood pressure in many experimental models of hypertension [245]. Oxidative stress is also linked to human hypertension. Population studies indicate increased systemic oxidative stress biomarkers in hypertensive patients, correlating oxidative stress with a higher risk of hypertension even in normotensive individuals [247]. A cross-sectional study involving 1,793 individuals with normal and hypertensive blood pressure found that the rs7770619 C > T polymorphism in the PPARD gene was closely associated with the oxidative stress biomarker malondialdehyde (MDA) in plasma, a risk factor for hypertension. Individuals with the CT genotype had lower hypertension risk, systolic blood pressure, blood glucose, and plasma MDA levels than those with the CC genotype, suggesting that the PPARD rs7770619 SNP could be a potential candidate gene for hypertension [248].

Most cancer risks, including lung cancer, arise from uncontrolled factors, such as environmental pollution, toxins, and free radicals, that lead to oxidative stress—often induced and accumulated by smoking. These factors, combined with environmental pollutants and toxins, contribute to genetic alterations [249]. Cigarette smoke is a primary cause of inflammatory cell recruitment, leading to alterations in inflammatory cytokine secretion, making individuals susceptible to lung cancer. A key factor in this process is the excessive accumulation of ROS caused by smoking. These radicals and ROS may result from moderate leakage in the mitochondrial electron transport chain, endoplasmic reticulum, and chloroplasts. The imbalance between ROS and the antioxidant defense system leads to oxidative stress within cells, oxidizing functional biomolecules, damaging cells, and causing tissue injury [249, 250]. Studies have identified three SNPs (rs1695, rs2333227, rs699512) in oxidative stress-related genes that are significantly associated with overall survival in advanced NSCLC patients treated with EGFR TKIs. These genetic variations in SNPs affect patient response to treatment, exhibiting a gene-dosage effect [251]. Additionally, the rs662 polymorphism in the PON1 gene shows a significant interaction between smoking, lung cancer risk, and oxidative stress. Individuals with the rs662 AA genotype have a lower lung cancer risk in non-smokers and lower levels of the oxidative stress marker 8-OHdG, suggesting that PON1 gene polymorphisms co-regulate lung cancer occurrence and oxidative stress levels in conjunction with environmental factors [252]. These findings indicate that oxidative stress-related genetic variations play an important role in lung cancer prognosis and hypertension.

Metabolic disorder

Metabolic dysregulation is a key mechanism in both hypertension and lung cancer, particularly involving energy metabolism, lipid metabolism, and glucose metabolism [253–258]. These metabolic pathways not only drive the progression of each disease independently but are also interconnected through shared biological mechanisms. In hypertension, patients often exhibit abnormalities in energy metabolism, particularly in vascular smooth muscle and endothelial cells. Mitochondrial dysfunction leads to insufficient ATP (adenosine triphosphate) production, affecting the balance of vascular contraction and relaxation. Energy deficits result in impaired smooth muscle cell contractility, reducing vascular regulation and leading to sustained vascular constriction and elevated blood pressure. Dysregulated glucose metabolism can also contribute to hypertension by promoting insulin resistance, which activates the sympathetic nervous system and increases norepinephrine secretion, further inducing vasoconstriction and raising blood pressure [258–260]. Moreover, lipid metabolism disorders are closely associated with hypertension, particularly elevations in cholesterol, triglycerides, and low-density lipoprotein. These lipids deposit on vascular walls, facilitating atherosclerotic plaque formation and increasing vascular resistance. Atherosclerosis reduces vascular elasticity, impairs blood flow, and contributes significantly to the development and progression of hypertension [261]. Metabolic imbalances, especially in lipid and glucose metabolism, are often accompanied by increased ROS, leading to oxidative stress that further damages the vascular endothelium, inhibits NO production, and impairs vascular regulation [262, 263]. For example, adipose tissue is closely linked to metabolic hypertension, and in obesity, excess free fatty acids and inflammatory adipokines from fat tissue damage the vascular endothelium, increasing blood pressure [264]. Obesity also promotes renal sodium reabsorption and activates the sympathetic and renin-angiotensin systems, raising blood pressure [265].

In lung cancer and other malignancies, cellular metabolism undergoes significant alterations, with the “Warburg effect” being the most prominent. Cancer cells rely on glycolysis for energy production, even in the presence of oxygen, rather than oxidative phosphorylation. This metabolic reprogramming supports rapid cancer cell proliferation, as glycolysis not only supplies energy but also provides metabolic intermediates necessary for cellular growth. This phenomenon enhances cancer cell proliferation and promotes tumor growth [266–268]. Lipid metabolism dysregulation also plays an important role in lung cancer. Cancer cells require large amounts of fatty acids to support cell membrane synthesis and signaling. The activation of lipid synthesis pathways accelerates cancer cell proliferation, while lipid peroxidation in metabolic processes can increase oxidative stress, promoting cancer progression [269, 270]. In addition to directly impacting cancer cells, metabolic changes affect the surrounding microenvironment. With the advent of new cancer therapies targeting the immune microenvironment, these metabolic changes may influence both cancer progression and therapeutic responses [271]. In small cell lung cancer (SCLC) patients, genetic variations in glutathione metabolism and DNA repair pathway genes have been significantly associated with survival. SNPs in genes such as GSS, ABCC2, and XRCC1 affect metabolic and DNA damage repair capacities, modulating patient response to treatment and impacting prognosis. Metabolic dysregulation plays a shared pathogenic role in hypertension and lung cancer, highlighting the potential for targeted metabolic interventions [272]. Interventions aimed at correcting metabolic imbalances, such as the use of antioxidants and metabolic regulators, may help improve outcomes in both diseases.

Critical synthesis of genetic, epigenetic, and environmental evidence

The comorbidity of hypertension and lung cancer emerges from a complex interplay of genetic predisposition, epigenetic regulation, and environmental exposures. While each of these domains has been extensively discussed individually, it is their convergence that underlies the shared pathophysiological mechanisms observed in clinical and molecular studies.

Genetic susceptibility plays a foundational role, with shared polymorphisms and risk loci—such as MALAT1, ALDH2, and JMJD3—implicated in both vascular and oncogenic pathways. These genes affect cellular functions ranging from vascular remodeling and immune modulation to metabolic reprogramming and tumor progression. Importantly, the expression and impact of these genetic factors are further modulated by epigenetic mechanisms such as DNA methylation and histone modifications [49, 53–55, 59, 273]. For instance, genes like KCNK3 and GAS5 demonstrate dual functionality in both blood pressure regulation and tumor suppression, highlighting epigenetic plasticity as a mediator of comorbid disease risk [69, 70, 274–276]. Environmental exposures such as PM2.5, smoking, and alcohol consumption act as external stressors that synergize with genetic and epigenetic mechanisms to amplify disease susceptibility. Many of these agents induce oxidative stress, inflammation, and immune dysregulation, thereby acting as convergent drivers of both hypertension and lung cancer. For instance, PM2.5 has been shown to contribute to endothelial dysfunction and DNA methylation changes, linking vascular injury with tumorigenic processes.

This convergence is further supported by overlapping biological pathways such as chronic inflammation, endothelial dysfunction, oxidative damage, and immune escape—pathways that are reinforced by both intrinsic (genetic/epigenetic) and extrinsic (environmental) inputs. The gene–environment–epigenome axis thus provides a compelling framework for understanding the molecular underpinnings of this comorbidity [12, 277–281]. This relationship is visually represented in Fig. 3. These findings highlight the synergistic effects of genetic and environmental factors, which can guide targeted clinical approaches. From a clinical perspective, individuals with high genetic risk profiles—particularly those exhibiting susceptibility to chronic inflammation or endothelial dysfunction—who are exposed to adverse environmental conditions should be considered priority candidates for early screening and preventive strategies. Such stratification may significantly improve outcomes in patients susceptible to both hypertension and lung cancer.

Fig. 3.

Schematic summary of environmental exposures and shared mechanisms between hypertension and lung cancer. This figure provides a schematic overview of the comorbidities of hypertension and lung cancer, illustrating the interplay of genetic factors and environmental exposures in driving shared biological mechanisms. Environmental exposures, including air pollution (e.g., PM2.5), radon, diet habits, occupational exposure, smoking, and other exposures, are depicted with corresponding icons and linked to their influence on disease development. Genetic factors contribute to susceptibility, while common biological mechanisms—such as vascular endothelial dysfunction, immune dysregulation, metabolic disorder, oxidative stress, and inflammation—form the central pathway connecting the two conditions. The diagram emphasizes the synergistic role of genetic, epigenetic, and environmental factors in the pathogenesis of this comorbidity

Conclusion

Hypertension and lung cancer are two of the most common and burdensome chronic diseases globally. Their coexistence poses complex challenges in both biomedical research and clinical practice, with mounting evidence suggesting shared pathogenic mechanisms. This review synthesizes current knowledge, highlighting shared genetic, epigenetic, and environmental factors as the underlying basis of these diseases. Mechanisms such as inflammation, oxidative stress, vascular dysfunction, and metabolic dysregulation are central to this comorbidity. These shared pathways not only elucidate the intricate interplay between hypertension and lung cancer but also provide potential avenues for integrated therapeutic strategies.

While some important scientific questions have been addressed, several remain unanswered. For example, the precise role of gene-environment interactions in the comorbidity of hypertension and lung cancer is not yet fully understood. Additionally, how external exposures such as smoking, air pollution, and dietary habits influence disease progression through molecular and cellular pathways remain poorly understood. In clinical terms, the comorbidity of hypertension and lung cancer significantly complicates disease management. Hypertension not only adds complexity to the pharmacological treatment of lung cancer but also contributes to poorer outcomes for affected patients. Personalized medicine approaches, driven by biomarkers and genetic risk profiles, may help optimize treatment strategies for this high-risk population.

The study of comorbidity between hypertension and lung cancer faces several challenges. First, the pathological mechanisms of these two diseases are markedly different. Hypertension primarily involves vascular dysfunction, chronic inflammation, and metabolic dysregulation, while lung cancer is driven by processes such as cell proliferation, genetic mutations, and immune evasion. Effectively integrating these disparate mechanisms and exploring their interactions in the context of comorbidity remains a significant research challenge. Secondly, there is considerable individual variability among patients, especially in those with both hypertension and lung cancer, leading to significant differences in disease presentation, progression rates, and treatment responses. This heterogeneity complicates clinical studies, making data analysis and the generalizability of results more difficult. Moreover, current animal models are limited in their ability to fully replicate the complex pathological state of hypertension and lung cancer comorbidity, which hampers experimental design and interpretation. Finally, the lack of long-term clinical follow-up data means that effective interventions and treatment strategies for managing the comorbidity of hypertension and lung cancer have not yet been fully validated. Addressing these challenges will require interdisciplinary collaboration and the development of more robust experimental and clinical research frameworks to advance our understanding and treatment of this comorbidity.

Future research should focus on integrating polygenic risk scores with environmental exposure metrics—such as long-term PM2.5 levels, radon, and occupational chemicals—to quantify cumulative disease risk. Additionally, identifying dual-function molecular regulators using large-scale population-based multi-omics datasets could enable the discovery of shared biomarkers and therapeutic targets. A second pressing need lies in developing robust in vivo and in vitro models to accurately simulate the comorbid disease state. Novel approaches such as organoids, vascularized tumor-on-chip models, and genetically engineered mouse models with inducible vascular and oncogenic mutations may better replicate the interplay between tumor biology and cardiovascular stress. Clinically, prospective cohort studies with detailed phenotyping and longitudinal follow-up are essential to evaluate how coexisting hypertension alters lung cancer progression, response to therapy (e.g., immunotherapy resistance), and overall prognosis. These studies should incorporate stratification by smoking status, sex, and treatment regimens to disentangle confounding effects. From a translational perspective, integrative biomarker panels combining genetic, epigenetic, and exposure data could enable early risk prediction and patient stratification. Artificial intelligence and machine learning models may facilitate the development of personalized screening and treatment strategies tailored to individuals with dual risk profiles. Public health efforts should also emphasize targeted education, early screening, and environmental control policies in high-risk regions—particularly those affected by combined air pollution and occupational exposures.

In conclusion, the association between hypertension and lung cancer is not only a critical focus of scientific research but also an urgent challenge for clinical practice. By advancing our understanding of the mechanisms underpinning their comorbidity, leveraging innovations in precision medicine, and fostering interdisciplinary collaboration, we can improve survival rates and quality of life for affected patients while mitigating the global health impact of these diseases.

Author contributions

Jingtong Zeng, Ying Chen conceived and designed this manuscript, Ying Chen obtained the funding. Wenxun Dong, Daqian He collected the data and prepared the figures. Difang Shi, Zhenghong Yang participated the discussion and revised the manuscript. All authors approved the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82060426; No. 82272980; No. 82360562); The “Key R&D Program” (Project No. 202403AC100015); The “First-Class Discipline Team Construction Project” of Kunming Medical University for the Environmental, Genetic, and Lung Cancer Pathogenesis Research Team (Project No. 2024KKTDPY07); First-Class Discipline Team of Kunming Medical University (2024XKTDYS07); Yunnan Provincial Chest Tumor Prevention and Treatment Research Innovation Team (No. 202405AS350015); Development of Precision Prevention and Full-Cycle Intelligent Management System for Regionally High-Incidence Lung Cancer in Yunnan (No. 202303AC100203).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.