ADAR1-Mediated RNA Editing Regulates Innate Immunity in Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder defined by elevated pulmonary pressures, distal arterial remodeling, and eventually right ventricular failure¹. Although heterogeneous, PAH reflects coordinated dysfunction in endothelial and smooth muscle compartments. Endothelial perturbations alter barrier integrity, inflammatory cascade, and vasoactive balance, while smooth muscle proliferation and phenotypic modulation drive medial thickening and elevated vascular resistance^2–4. Growing attention has turned toward epitranscriptomic regulation as a potential determinant of vascular homeostasis.

Among these mechanisms, adenosine-to-inosine (A-to-I) editing, catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes, has emerged as a key regulator of RNA structure and innate immune recognition^{5, 6}. ADAR1, the most broadly expressed catalytic member of the family, exists as two isoforms: the nuclear p110 and the type I interferon-inducible cytoplasmic p150 isoforms, both of which limit the accumulation of immunogenic double-stranded RNA (dsRNA). When ADAR1 activity declines, unedited dsRNA engages cytosolic sensors such as MDA5, triggering type I interferon pathways and inflammatory activation⁷. Although this mechanism is implicated in multiple inflammatory and vascular diseases^8–10, its contribution to pulmonary vascular biology has remained underexplored.

In this issue of Circulation Research, two complementary studies by Kim et al.¹¹ and Woodcock et al.¹² begin to fill this gap and identify ADAR1 as a regulator of both smooth muscle and endothelial responses in pulmonary hypertension (Figure 1).

Figure 1. ADAR1 deficiency orchestrates cell-type-specific innate immune activation in the pulmonary vasculature, promoting inflammation and pulmonary hypertension.

Schematic overview illustrating convergent findings from Woodcock et al. and Kim et al. demonstrating that loss of ADAR1-dependent A-to-I RNA editing dysregulates both endothelial and smooth muscle compartments. Left (PAECs): Reduced ADAR1 expression leads to accumulation of unedited NOCT transcripts, enhancing mRNA stability and upregulating NOCT and IRF7, which drive type I interferon signaling, endothelial apoptosis, and immunoactivation. Right (PASMCs): Impaired RNA editing causes intracellular accumulation of endogenous dsRNA, activating MDA5-mediated sensing and PKR signaling, resulting in increased IRF3/7 activation, IFNβ production, and eIF2α phosphorylation. These responses promote inflammatory crosstalk and macrophage recruitment. Together, endothelial and smooth muscle dysfunction contribute to vascular inflammation and further promote pulmonary arterial remodeling and PH pathogenesis. Abbreviations: ADAR1, adenosine deaminase acting on RNA 1; dsRNA, double-stranded RNA; eIF2α, eukaryotic translation initiation factor 2 alpha; IFNβ, interferon beta; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; MDA5, melanoma differentiation-associated protein 5; PASMC, pulmonary artery smooth muscle cell; PAEC, pulmonary artery endothelial cell; NOCT, nocturnin; PH, pulmonary hypertension; PKR, protein kinase R. Created with BioRender.com.

Kim et al.¹¹ offer a compelling illustration of how impaired RNA editing reprograms pulmonary artery smooth muscle cells (PASMCs) in PAH. Their analysis of patient-derived PASMCs reveals that editing loss is not diffuse but concentrates within 3′ untranslated regions. Accumulated unedited dsRNA engages MDA5 and activates a type I interferon program. The authors extend these findings in vivo using a tamoxifen-inducible Adar1^SMC-KO model. Here, the absence of ADAR1 profoundly intensifies and exacerbates hypoxia-induced PH: right ventricular pressures rise, right ventricular hypertrophy is more pronounced, and distal arterioles exhibit deeper muscularization. Histological analyses reveal medial thickening, perivascular inflammation, vascular leak, and impaired endothelial barrier integrity. A notable strength of the study is its attention to cell-cell communication using conditioned media. Mechanistically, ADAR1-deficient SMCs release sustained interferon-β, polarizing macrophages toward an M1 phenotype and amplifying inflammatory crosstalk. Treatment with 2BAct, an activator of eIF2B that mitigates protein kinase R (PKR)-driven translational arrest, reduces inflammation and improves hemodynamics, underscoring the therapeutic relevance of the dsRNA-interferon axis in PH.

Woodcock et al.¹² shift the spotlight to the endothelium, where they find that ADAR1 is the predominant editing enzyme in pulmonary artery endothelial cells (PAECs) and is substantially reduced in endothelial cells derived from multiple forms of human PH, including Group 1 and Group 3. Loss of ADAR1 in cultured ECs unleashes robust type I interferon activation and elevates IL-6 expression. To decipher the role of endothelial ADAR1, the authors used both genetic (Adar1^K999N) and pharmacologic (8-azaadenosine) approaches that selectively impair editing. Across models, diminished RNA editing worsens PH severity, increases muscularization of distal arterioles, and augments vascular remodeling, establishing editing loss as a pathogenic driver. The mechanistic centerpiece of this work is the identification of nocturnin (NOCT). Known primarily for its role in metabolic and circadian biology, NOCT is surprisingly recast here as a facilitator of interferon regulatory factor 7 (IRF7), a transcriptional amplifier of antiviral and inflammatory responses. In ADAR1-deficient ECs, NOCT upregulation is both necessary and sufficient to promote IRF7 activation, endothelial apoptosis, and barrier instability. Endothelial-specific deletion of NOCT interrupts this cascade, attenuating interferon signaling and improving vascular and hemodynamic outcomes in vivo. Perhaps the most provocative element of the study is the demonstration that restoring ADAR1 expression, via endothelial-targeted AAV6 delivery, can reverse established monocrotaline-induced PH. This finding suggests that RNA editing is not merely a modifier of early disease or disease progression but a critical mechanism with therapeutic potential even in advanced remodeling.

Despite their cell-specific mechanisms, both studies converge on a shared biological principle: loss of ADAR1 unleashes a feed-forward inflammatory circuit that destabilizes the pulmonary vasculature. In SMCs, unedited dsRNAs activate MDA5 and promote interferon-β-driven macrophage polarization. In endothelial cells, loss of editing triggers the NOCT-IRF7 axis, cell apoptosis, barrier dysfunction, and inflammatory signaling. Together, these pathways create a pro-inflammatory microenvironment, reinforcing multilayer injury across the arterial wall.

Looking forward, these findings raise several timely questions that naturally extend the biology revealed in both studies. Does RNA editing change in response to environmental stressors, such as hypoxia or viral infection? Could sex-dependent differences in editing contribute to PAH’s well-recognized sex bias? And how do editing-dependent pathways intersect with other RNA modifications, including m⁶A, that regulate vascular plasticity? Furthermore, the identification of NOCT as a novel editing-dependent mediator of endothelial inflammation also invites consideration of its broader circadian roles. Indeed, increasing evidence suggests that circadian rhythms modulate immune responses in pulmonary diseases¹³. In line with previous studies, timing-dependent differences in therapeutic efficacy have been documented in cancer studies¹⁴. Whether RNA editing capacity, or ADAR1-NOCT signaling, fluctuates across the circadian cycle is unknown, but even this possibility suggests an unexplored temporal dimension to inflammatory vulnerability and therapeutic responsiveness in PH.

Collectively, the studies by Kim et al.¹¹ and Woodcock et al.¹² show that loss of ADAR1 ignites inflammatory signaling that reshapes the pulmonary vasculature. Together, they broaden our understanding of how innate immunity drives PH and point toward RNA editing as a potential therapeutic target. A key next step is to determine whether ADAR1 dysregulation emerges early as a trigger of disease or develops later as a response to vascular stress. It will also be essential to define whether editing-dependent molecular patterns can serve as practical biomarkers for diagnosis, risk stratification, or treatment monitoring. As these translational questions are addressed, RNA editing may evolve from a mechanistic insight into a clinically actionable pathway. This positions ADAR1 as a central guardian of vascular immune balance and highlights RNA editing as a promising frontier for next-generation PH therapies.