Lung cancer represents the most frequent cancer and the leading cause of cancer-related mortalities deaths worldwide in 2022 [1]. Unfortunately, both incidence and mortality rates are expected to rise further in the coming decades [2]. Lung adenocarcinoma (LUAD), which accounts for nearly half of all lung cancer cases, is the predominant subtype [3]. Most LUAD patients are diagnosed at advanced stages, often missing the opportunity for curative resection. As a result, 30–55 % of patients experience metastasis or recurrence and face a poor prognosis after surgery [4], [5]. Relevant epidemiological data indicates that LUAD patients have a 5-year survival rate of less than 20 % even after receiving conventional treatments [6], [7]. This underscores the urgent need for more effective therapeutic options.

LUAD's high resistance to conventional chemotherapy and radiotherapy remains a major obstacle to improving treatment outcomes. As a result, cell death-based therapies have been proposed as promising strategies for future treatment approaches [8]. Ferroptosis, a recently discovered form of regulated, iron-dependent cell death, is characterized by distinctive molecular changes and morphological features [9]. The hallmark of ferroptosis includes cell membrane rupture and cell death, driven by cystine depletion and the accumulation of iron-dependent lipid peroxides [10]. This form of cell death has been shown to play a role in tumor development and modulate treatment responses across various cancer types [11]. Increasing evidence suggests that inducing ferroptosis or manipulating ferroptosis-related genes can inhibit the growth of tumor cells and counteract resistance to drugs, including in LUAD [12].

The p21-activated kinase (PAK) family consists of serine/threonine kinases characterized by a Cdc42/Rac-interactive binding domain and a Ste20-related kinase domain [13]. These kinases are involved in various essential cellular processes, including cell motility, survival, and gene regulation [14], [15]. In the context of cancer, PAKs play pivotal roles in mediating cancer-promoting signals from cell surface receptors and in modifying interactions with the broader signaling network and other proteins [16]. Among these, PAK6 is a distinct member of the type II PAK family and was first identified as an androgen receptor-interacting protein [17], [18]. Recent research has highlighted the significant oncogenic potential of PAK6 in a variety of cancers, including cervical cancer [19], esophageal squamous cell carcinoma [20], and breast cancer [21]. Nevertheless, the function of PAK6 in LUAD remains unclear. Specifically, Chen et al. reported in 2022 that PAK6 loss contributed to epithelial cell ferroptosis in ulcerative colitis [22], suggesting the potential involvement of PAK6 in ferroptosis resistance.

Building on these insights, this study aims to explore the role of PAK6 in the malignant properties of LUAD cells, with a particular focus on its involvement in ferroptosis resistance. Additionally, the study will examine the interactions and effects of pumilio RNA-binding family member 1 (PUM1), a potential RNA-binding protein (RBP) of PAK6 in LUAD, as suggested by bioinformatics analyses.