Pulmonary hypertension (PH) is a progressive disorder characterized by elevated pulmonary arterial pressure and vascular remodeling, culminating in right heart failure and premature mortality. Globally, PH imposes a significant economic burden, with an estimated prevalence affecting approximately 1% of the population (1).

PH encompasses five distinct clinical subtypes: group 1 pulmonary arterial hypertension (PAH), group 2 PH associated with left heart disease (PH-LHD), group 3 PH associated with lung diseases and/or hypoxia, group 4 PH associated with pulmonary artery obstruction, and group 5 PH with unclear and/or multifactorial mechanisms. The pathogenesis of PAH is intricately multifaceted, involving a spectrum of mechanisms, such as endothelial cell dysfunction, aberrant smooth muscle cell proliferation, plexiform lesions, inflammation, immune responses, cytokine activity, chronic thrombosis, small vessel occlusion, anti-apoptotic processes, as well as metabolic and hormonal influences (2). Currently, the most commonly studied animal models primarily replicate Group 1 and Group 3 PH. This review primarily focuses on Group 1 PH. Patients with PAH are hemodynamically defined by pre-capillary PH, except in cases of other underlying causes of pre-capillary PH (1). Although targeted therapies have significantly improved the prognosis of PAH patients, it remains a challenge to reduce pulmonary arterial pressure to normal levels and reverse pulmonary vascular remodeling. Targeted therapies for PAH primarily target three pathways: endothelin receptors on pulmonary arterial smooth muscle cells (PASMCs), which promote vasoconstriction and cell proliferation; the nitric oxide-induced activation of soluble guanylate cyclase (sGC); and the prostacyclin metabolic pathway. Therefore, calcium channel blockers are used to treat PAH patients who show a positive response to acute vasoreactivity testing (1). There are also new drugs under clinical investigation that target other pathways and have been reported to improve patient symptoms and hemodynamics (2)^. With these therapies, 5-year survival improved by more than 60% in 2015 (3). However, these drugs cannot reverse vascular remodeling, although they function by inducing vasodilation to alleviate clinical symptoms. Therefore, it is crucial to explore the pathophysiological mechanisms of PAH in order to provide early interventions and improve prognosis.

Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) is an RNA-binding protein (RBP) that regulates the mRNA expression of several genes and exhibits diverse biological effects, making it a potential therapeutic target for multiple diseases.

The role of HNRNPA2B1 has primarily been studied in the field of cancer. The mechanisms driving PAH development partially overlap with those of carcinogenesis. Cell proliferation and anti-apoptotic phenotypes are also key features of PAH. HNRNPA2B1 can promote cell proliferation and prevent apoptosis through various pathways, and it can also promote tumor cell proliferation through mechanisms such as epithelial-mesenchymal transition (EMT) and angiogenesis (4, 5). However, its role in PAH was not elucidated until 2022. Silencing of HNRNPA2B1 can mitigate monocrotaline (MCT)-induced PAH in rats (6). Moreover, HNRNPA2B1 is upregulated and localized in the nucleus of patients with idiopathic pulmonary hypertension (IPAH), where it participates in the development of PAH by regulating the cell cycle (6). However, the detailed mechanisms remain under investigation. HNRNPA2B1 has been reported to promote proliferation and prevent apoptosis by activating the STAT3 and Erk1/2 signaling pathways (7). Importantly, these two signaling pathways are also crucial for promoting proliferation and preventing apoptosis in PASMCs (8, 9). Furthermore, HNRNPA2B1 regulates the maturation of mRNA precursors by recognizing the N6-methyladenosine (m6A) post-transcriptional modification (10). It is also associated with the exosomal secretion of miRNAs in endothelial cells (ECs) (11). Currently, miR-424/503 has been identified as an important component of pulmonary vascular EC homeostasis, and miRNAs may serve as potential targets for treating PAH (12–15). HNRNPA2B1 may also contribute to the occurrence of PAH partly through these pathways. Although HNRNPA2B1 expression in pulmonary arterial endothelial cells (PAECs) is not significantly different from that in normal control cells (6), it may still exert its effects in PAH ECs by sorting and exporting specific miRNAs. In conclusion, HNRNPA2B1 shows great potential as a therapeutic target for PAH. We have comprehensively reviewed and presented the potential mechanisms through which HNRNPA2B1 drives the development of PAH.

HNRNPA2B1 is a member of the heterogeneous nuclear ribonucleoprotein (HNRNP) family. Structurally, HNRNPA2B1 consists of two RNA recognition motifs (RRMs) located at its N-terminus, referred to as RRM1 and RRM2, and a C-terminal low-complexity region rich in glycine residues, which includes an RGG box, a core PrLD domain, and an M9 nuclear localization signal (M9-NLS) (16). The RRMs and the RGG box are crucial for RNA binding (16, 17). HNRNPA2B1 can bind to specific m6A-modified regions on mRNA through its RRM domains, thereby mediating the translation and degradation of downstream mRNA (18). Although the RGG box significantly affects binding strength, its impact on specific RNA binding is relatively small (19). HNRNPA2B1 plays a role in mRNA splicing, mRNA modification, promotion of pre-mRNA synthesis, transport of mature mRNA, and maintenance of mRNA stability; therefore, its role spans almost the entire process, from mRNA synthesis to maturation (10, 20, 21). As an m6A reader, HNRNPA2B1 can recognize the m6A-specific motifs RGAC and interact with the microprocessor complex protein DGCR8, regulating selective splicing and processing of target mRNAs (10). HNRNPA2B1 may regulate the splicing and processing of target mRNAs by recognizing m6A, thereby activating or inhibiting downstream mechanisms involved in various pathophysiological processes.

HNRNPA2B1 was initially discovered as a tumor-associated antigen in non-small cell lung cancer (22, 23). Patients with non-small cell lung cancer who are positive for HNRNPA2B1 have a worse prognosis (24). HNRNPA2B1 is involved in various pathological and physiological processes, including inflammation (25), immunity (26), oxidative stress, cell proliferation, apoptosis (27), EMT (28), and metabolism (29). It is implicated in the development of various diseases such as cancers, rheumatic immune system diseases, neurological disorders, and viral infections (30). However, few studies have elucidated the relationship between PAH and HNRNPA2B1. Research suggests that HNRNPA2B1 may play a potential role in the underlying mechanisms of PAH. Pulmonary vascular remodeling is a basic pathological feature in all groups of PH. In PAH, the affected vessels are small arteries, whereas in conditions like pulmonary venous obstructive disease, pulmonary capillary hemangiomatosis, or PH-LHD, the medium-sized veins and capillaries are primarily involved. It is characterized by the accumulation of different vascular cells (PASMCs, PAECs, fibroblasts, myofibroblasts, and pericytes) in the pulmonary artery wall, as well as the disappearance of precapillary arterioles and excessive infiltration of inflammatory cells around the vessels, such as B and T lymphocytes, mast cells, dendritic cells, and macrophages (31). The underlying mechanisms include abnormal proliferation and migration of PASMCs, dysfunction of ECs, infiltration of inflammatory cells, activation of fibroblasts in the vascular adventitia, and accumulation of extracellular matrix, all contributing to structural changes in the vessel wall. As an RNA-binding protein, HNRNPA2B1 is involved in pathological processes such as cell proliferation, migration, angiogenesis, EMT, cell metabolism, and inflammation through mechanisms including the regulation of gene transcription, m6A modification, miRNA sorting, and exosome secretion. HNRNPA2B1 has been implicated in the pathological mechanisms of various cell types, including smooth muscle cells (6, 32, 33), endothelial cells (11, 34), fibroblasts (35), and macrophages (36). Therefore, HNRNPA2B1 may contribute to pulmonary vascular remodeling by modulating the pathological processes in these cells.

This review article highlights the potential mechanisms of HNRNPA2B1 in the pathogenesis of PAH. Figure 4 illustrates how HNRNPA2B1 may influence pulmonary hypertension by regulating PASMCs, PAECs, and macrophages. To date, only one study has demonstrated the role of HNRNPA2B1 in MCT-induced PH, though the specific mechanisms remain unexplored. Numerous studies suggest that HNRNPA2B1 is involved in cell proliferation, apoptosis, and PASMC metabolism (Figure 1); however, its exact mechanism of action in PASMCs is still unclear. The pathophysiology of PAH is complex, and the MCT-induced PH model fails to fully replicate the clinical features observed in PAH patients. Whether the proposed mechanisms can be generalized to other experimental models remains uncertain. Currently, no drugs targeting HNRNPA2B1 for PAH treatment exist. While gene knockdown models show promise in animals, their translational relevance to humans has yet to be established, underscoring the need for further research.

Additionally, the regulatory role of HNRNPA2B1 in EC function is poorly characterized. Although studies report no significant difference in HNRNPA2B1 expression in PAECs from PAH patients, it may still modulate exosome-mediated miRNA sorting mechanisms in ECs (Figure 2). Research on HNRNPA2B1-PAEC interactions in PAH remains in its early stages.

Structurally, the A2 and B1 isoforms of HNRNPA2B1 differ by only a 12-amino acid sequence, yet they exhibit distinct RNA-binding preferences. The ratio of these isoforms may vary across tissues and pathological stages, necessitating deeper functional characterization of this molecule (Figure 3).

Finally, HNRNPA2B1 regulates the Warburg effect and macrophage polarization—processes implicated in PAH progression. Nevertheless, the discussion of the relationship between HNRNPA2B1 and PAH is speculative, and there is currently no direct evidence to establish a connection between them. Therefore, further investigations are required to delineate its role in PAH mechanisms.

In summary, HNRNPA2B1 acts as an RBP through m6A-dependent mechanisms and regulates cell proliferation, apoptosis, metabolism, the immune microenvironment, and angiogenesis, all of which are important for the development of PAH. It is involved in the entire process, from mRNA generation to maturation, as well as in miRNA exosome sorting. However, the specific mechanisms need further confirmation. Targeted therapy involving HNRNPA2B1 is promising, but still in its early stages. Efforts to design and optimize treatment strategies targeting HNRNPA2B1 should continue.