Lung cancer, the second most frequently detected cancer in the United States, experienced a total of approximately 220,000 newly estimated cases in 2019, thereby constituting nearly 13% of all cancer diagnoses [1]. Lung cancer affects one in 15 men and one in 17 women over the course of their lifetime and tends to be diagnosed at an average age of 70 years. The five-year survival rate of patients with lung cancer that has spread to other parts of the body is only 5%. Clinical manifestations of lung cancer may appear in the form of persistent cough, chest discomfort, weight loss, general feeling of illness, breathing difficulties, accumulation of fluid in the pleural space, pneumonia, chronic obstructive pulmonary disease, or pulmonary fibrosis [2], [3]. Based on history and methods of diagnosis and treatment, lung cancer is classified into two main types including small cell lung cancer (15% of all cases) and NSCLC, which accounts for about 80-85% of all cases [4]. The three main types of NSCLC are epidermoid or squamous cell carcinoma (SCC), large cell carcinoma (LCC), and adenocarcinoma. SCCs develop in the lungs, adenocarcinomas in alveolar cells, and LCCs in other areas of the lungs. Most people with early-stage NSCLC miss the ideal timing for treatment because of the absence of clinical presentations [5].

For those with NSCLC stage I–II, surgery is the advised course of treatment. High-dose stereotactic body radiation therapy produced good local tumor control and minimal toxicity for patients with clinical stage I NSCLC who are medically contraindicated for surgical resection or who refuse surgery [6], [7]. Molecular targeted therapy has proven beneficial for patients with neoplasms that exhibit particular genetic abnormalities. Platinum-based doublet therapy, with or without bevacizumab, continues to be the conventional first-line treatment for patients with advanced NSCLC who do not have a recognized molecular targeted therapy. Be aware that squamous cell histology is not a suitable use case for bevacizumab [6], [8]. Chemotherapy can increase survival rates for patients with advanced lung cancer while also producing cures for early-stage lung tumors [9]. With up to twenty treatments being authorized by the FDA, targeted medicines are still being developed, and targeted therapy along with chemotherapy have greatly improved patient outcomes. However, treating those suffering from metastatic NSCLC has become extremely difficult due to resistance brought on by genetic changes in cancer drivers [10], [11].

The development of NSCLC is associated with changes in different signaling pathways such as PI3K and mitogen-activated protein kinase (MAPK), which are linked to mutations in many genes such as epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase catalytic alpha (PIK3CA), and phosphatase and tensin homolog (PTEN), etc [12]. The presence of different molecular involvement in the formation of tumors leads to the different nature of this disease. Additionally, molecular and genetic changes may be found in different regions of the same tumor, which is called intratumoral heterogeneity [13]. Understanding the molecular biology of NSCLC has contributed to the development of treatments, particularly EGFR inhibitors [14]. However, new treatment strategies and drugs need to be developed to increase the survival rate of cancer patients.

PI3K, a group of lipid kinases, plays a vital role in variety of cellular processes by regulating the lipid-binding domains of intracellular signaling proteins [15]. PI3K proteins are categorized into three groups (I, II, and III) based on their structure and substrate preference. Class I PI3Ks, known for their responsiveness to extracellular signals, comprise PI3K class IA proteins, including the p85 regulatory subunit and p110 catalytic subunit. Dysregulation of these proteins has been implicated in many types of cancer. PI3K acts as a platform for several signaling kinases, such as AKT, a serine-threonine kinase, and phosphoinositide-dependent kinase (PDK)-1 [16]. AKT phosphorylates various molecules involved in cell cycle regulation (e.g., RAF-1 proto-oncogene, GSK3, FOXO, P21, P27), programmed cell death pathways (BAD, caspase 9, P27), and other important processes, such as blood vessel formation. Additionally, the PI3K/AKT pathway influences the response element-binding protein (CREB), IKK, and mouse double minute 2 homolog (MDM2) involved in the CAMP, NF-κB, and p53 signaling pathways, respectively [17]. The mammalian target of rapamycin complex 1 (mTORC1), a downstream effector of AKT, is activated by phosphorylation and is involved in protein synthesis regulation. PTEN acts as a regulator of the PI3K/AKT pathway by inhibiting PI3K activation through its lipid phosphatase activity [18]. PTEN phosphorylates phosphatidylinositol-3,4,5-trisphosphate (PIP3) and converts it to phosphatidylinositol-4,5-bisphosphate (PIP2). S6K1 downregulates mTORC1 and inhibits IRS1, thereby establishing a negative feedback loop in the PI3K/AKT pathway [19].

CircRNAs are a distinctive class of ncRNAs that lack 3′ and 5′ ends instead of forming a closed-loop structure, unlike linear RNAs. Initially, following their first identification in a virus by Sanger in 1976, circRNAs were dismissed as byproducts without any notable biological functions [20], [21], [22]. The specific role of circRNA in many physiological processes remains unclear. However, with the advent of RNA sequencing technologies in recent years, researchers have shown the significance of circRNAs in regulating gene expression and their involvement in the emergence and development of various diseases, including malignancies [23]. Moreover, previous studies have highlighted the conserved nature, stability, and abundant expression of circRNAs in tissues and exosomes. According to the qPCR and droplet digital PCR (ddPCR), a total of 343 circRNAs with differential expression were discovered between the plasma of patients afflicted with gastric cancer and that of healthy controls [24]. The extensive and consistent presence of circRNAs in both plasma and exosomes suggests their potential utility as biomarkers for prognosis and therapeutic interventions in cases of malignancy. A mechanism by which circRNAs serve as competitive endogenous RNAs (ceRNAs) for miRNAs. For example, circ_101237 can act as a sponge for miR-490-3p and boost MAPK1 expression, inhibiting cancer development and progression [25]. Additionally, certain circRNAs regulate the formation and progression of cancer by interacting with proteins. For example, circRNA_cIARS could inhibit cellular autophagy through its interaction with the protein RBP, ALKBH5 [26].

Different types of ncRNAs are involved in regulating numerous aspects of lung cancer, including cell growth, apoptosis, invasion, proliferation, and resistance to treatment [27]. Additionally, studies have shown that circRNAs interact with proteins, miRNAs, and other factors that influence gene expression and molecular pathways, suggesting their potential as targets for treating NSCLC in the future. In this review, we highlighted the recent research developments focusing on the molecular mechanisms and functional implications of circRNAs associated with the PI3K pathway in NSCLC progression.