Lung cancer, which is the most frequently identified cancer, exhibits the highest global incidence and fatality rates among all types of neoplasms [1]. Non-small cell lung cancer (NSCLC) represents the majority, around 85%, of lung cancer incidences and encompasses three primary histological categories, namely adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [2]. The frequency of NSCLC has been increasing, with lung adenocarcinoma (LUAD) emerging as a prominent histological subtype within NSCLC and accounting for approximately 60% of all cases of lung cancer [3]. The available treatment modalities for lung adenocarcinoma encompass targeted therapies, immunotherapy, radiotherapy, and chemotherapy [4]. Despite the advancements in therapies, such as platinum-based treatment and radiotherapy, the clinical outcomes for patients with LUAD remain suboptimal due to the challenges associated with delayed identification and the high incidence of metastasis [5]. Hence, elucidating the molecular pathways that underlie LUAD initiation and advancement would be advantageous for identifying novel diagnostic biomarkers and potential therapeutic targets.

The family of transmembrane proteins (TMEM) comprises a collection of proteins that attach to cellular membranes and span the entirety of the lipid bilayers, serving as pivotal gateways for regulating the selective transport of specific elements [6]. TMEM158 was initially recognized as a potential tumor growth suppressor, demonstrating specific activation throughout Ras-induced senescence in human diploid cells subjected to a retrovirus infection comprising RasV127 [7]. The TMEM158 overexpression has been observed in pancreatic malignancy and has been linked to adverse clinical outcomes as a result of its activation of the PI3K/AKT pathway [8]. In addition, the TMEM158 expression level and biological processes have been extensively documented across various forms of tumors. The TMEM158 overexpression has been detected in ovarian cancer, and it exerts a significant function in promoting the growth, invasion, adhesion, and tumorigenic potential of ovarian cancer cells [9]. Additionally, the ability of proliferating and migrating of colorectal cancer cells exhibited a significant reduction, while effectively suppressing multidrug resistance through inhibition of TMEM158 function [10]. Mohammed et al. [11] have also discovered that TMEM158 serves as a highly effective indicator for anticipating the efficiency of cisplatin therapy in individuals with NSCLC. Nevertheless, the investigation into the involvement of TMEM158 in LUAD and its underlying mechanism remains limited.

The objective of this investigation was to elucidate the potential role of TMEM158 in the progression and development of LUAD. A substantial association was observed between the TMEM158 expression and malignant features of LUAD cells, suggesting its potential for predicting prognosis in LUAD patients. Mechanistically, TMEM158 enhances the LUAD cell progression by stimulating the PI3K/AKT signaling pathways through TWIST1 activation.