Pulmonary arterial hypertension (PAH) is a progressive and life-threatening cardiovascular disorder characterized by sustained elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure(Huertas et al., 2018; Humbert et al., 2019). The condition arises from complex structural and functional changes within the pulmonary arterial system, including endothelial dysfunction, smooth muscle cell proliferation, and vascular remodeling. Despite considerable advances in our understanding and treatment of PAH, the disease continues to carry a poor prognosis, with high morbidity and mortality rates that remain largely unchanged over recent decades(Hassoun and Taichman, 2021; Hoeper et al., 2023). Current pharmacological approaches-such as vasodilators, endothelin receptor antagonists, phosphodiesterase-5 (PDE5) inhibitors, soluble guanylate cyclase (sGC) stimulators, and prostacyclin analogues provide symptomatic relief and modestly improve hemodynamic parameters. However, these therapies do not reverse pulmonary vascular remodeling nor fundamentally modify the disease course (Ciarka et al., 2007; Evans et al., 2021; Humbert et al., 2023; Khan et al., 2019; Trulock et al., 2007; Weatherald et al., 2022; Yusen et al., 2014). Consequently, elucidating the molecular and cellular mechanisms that drive pulmonary vascular remodeling is critical for developing next generation, disease modifying treatments with improved efficacy and safety profiles for patients with PAH.

Arachidonic acid 15-lipoxygenase (ALOX15) and its isoform, arachidonic acid 15-lipoxygenase type B (ALOX15B), are members of the lipoxygenase enzyme family. These non-heme iron-containing fatty acid dioxygenases are constitutively expressed in alveolar macrophages, airway epithelial cells, and vascular cells (Benatzy et al., 2022). ALOX15/15B metabolizes various polyunsaturated fatty acids (PUFAs) to generate bioactive lipid mediators (Weigert et al., 2018). Specifically, ALOX15/15B catalyzes the formation of 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] and 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], which are the principal metabolites of arachidonic acid (AA) (Benatzy et al., 2022). Accumulating evidence indicates that these ALOX15-derived metabolites, particularly 12(S)- and 15(S)-HETE, play crucial roles in the pathogenesis of PAH by promoting smooth muscle cell proliferation (Ran et al., 2014; Shan et al., 2012; Xing et al., 2018; Yu et al., 2015), inducing endothelial dysfunction(Liu et al., 2018; Ruffenach et al., 2020), driving pulmonary vascular fibrosis (Zhang et al., 2014) and exacerbating inflammation (Ross et al., 2015; Ruffenach et al., 2020). However, their specific roles in pulmonary artery endothelial cells (PAECs), particularly in the regulation of autophagy (a key process in the pathogenesis of PAH), remain unclear.

Autophagy is a fundamental cellular mechanism that maintains homeostasis by degrading and recycling damaged organelles and misfolded proteins. Increasing evidence suggests that dysregulated autophagy contributes to the development and progression of PAH(Chen, 2019; Zhang et al., 2019). However, the role of autophagy in PAH is complex and appears to vary depending on the stage of the disease. During the early phases, activation of autophagy may exert protective effects on pulmonary artery endothelial cells (PAECs) by preventing apoptosis and preserving endothelial function, thereby attenuating disease progression (Chichger et al., 2019). In contrast, persistent or excessive autophagy in advanced stages can lead to metabolic disturbances and enhanced inflammatory signaling, which may exacerbate vascular remodeling and worsen PAH(Bu and Singh, 2021; Mao and Ma, 2022). Clinical studies have reported conflicting findings, with both increased and decreased expression of autophagy-related proteins observed in patients with PAH, underscoring the multifaceted and context-dependent nature of autophagic regulation in this disease(Mao et al., 2023; Zhang et al., 2019).

Emerging evidence suggests a close interplay between autophagy and lipid metabolism in the pathogenesis of PAH(Chen et al., 2024a). Among the key mediators of lipid peroxidation, arachidonate ALOX15 and its isoform ALOX15B have attracted attention for their potential roles in regulating autophagy through the generation of lipid peroxides(Bouchaoui et al., 2023; Li et al., 2022). Notably, Li et al. (2018) reported that 12/15-lipoxygenase (12/15-LOX), a closely related enzyme, facilitates the formation of autophagic peroxide substrates, thereby implicating lipid peroxidation pathways in autophagic regulation. These findings raise the possibility that ALOX15 may similarly modulate autophagic activity in pulmonary vascular cells. However, the precise mechanisms through which ALOX15-mediated autophagy contributes to PAH pathogenesis remain unclear. The present study therefore seeks to elucidate the role of ALOX15 in endothelial autophagy and to determine how its activity influences pulmonary vascular remodeling during PAH progression.