Lung cancer (LC) is one of the most common cancers in the world and is the foremost cause of cancer-related mortality, characterized by high incidence and mortality rates (1). Non-small cell lung cancer (NSCLC) represents the predominant subtype of LC, comprising 80%-85% of cases (2). The occurrence of apoptosis plays an important role in the development of cancer, so it is particularly important to study the mechanism of apoptosis in NSCLC for therapeutic advancements. The mechanisms of apoptosis encompass endogenous pathways, which are activated by factors such as DNA damage, oxidative stress and a variety of other stress conditions, as well as extrinsic pathways, which are initiated by cell membrane proteins associated with death receptors (3, 4). Alterations in upstream regulatory factors within the two pathways may lead to the imbalance between cell proliferation and apoptosis (5).

Bibliometrics uses mathematical and statistical techniques to quantitatively and qualitatively assess publications within a given research domain, thereby facilitating the monitoring of research trends and serving as a diagnostic tool for the field (6, 7). Bibliometrics serves as a tool for assessing the current state of research, identifying research hotspots, and predicting future research trajectories (8). Citespace, a scientific visualization software package developed by Dr. Chaomei Chen from Drexel University, USA. It operates within a Java runtime environment and offers direct visual effects (9). VOSviewer is a software application designed for the construction and visualization of bibliometric maps. It also provides a viewer, which provides a detailed check on the scientific nature of cartography (10). The software is equipped with robust capabilities for conducting co-occurrence and co-citation analyses (11). Additionally, its data can be exported to SCImago Graphica for enhanced geographic visualization and collaboration analysis, thereby improving the aesthetic quality of the visual representations. Bibliometrix package of R software 4.3.1 serves as a comprehensive language and environment for performing statistical analyses and generating graphical representations of data (12). As a versatile analytical tool developed in R, Bibliometrix is particularly well-suited for the scientific mapping of bibliometric data (13).

The number of citations of an article serves as a significant metric for assessing its scholarly impact, with a high number of citations often indicating its recognition and validation within the academic community. Despite this, an analysis of the most influential articles in the domain of NSCLC apoptosis research has not yet been conducted. In this study, we selected the top 100 most frequently cited articles and analyzed their quality and characteristics in order to provide references for researchers.

This study seeks to identify the top 100 most-cited articles pertaining to the apoptosis of NSCLC over past two decades and to analyze their bibliometric characteristics. The volume of research on NSCLC apoptosis has shown a consistent upward trend in recent years, reflecting the growing scholarly interest in this area. To investigate the current state of research and emerging focal points within this domain, this study compiles and examines the most frequently cited articles from the past twenty years, thereby offering a valuable reference for future research endeavors.

LC ranks as the second most prevalent malignancy globally, with approximately 1,796,144 fatalities reported in 2020. The overall 5-year survival rate for LC patients ranges from 10% to 20% following diagnosis (1). However, for those diagnosed at stage IV, the 5-year survival rate diminishes to a mere 5%. Notably, the majority of patients are diagnosed at an advanced stage of the disease (121). The therapeutic approaches for NSCLC typically encompass surgical intervention, chemotherapy, radiotherapy, molecular targeted therapy, immunotherapy, among others (122). However, the emergence of personalized treatment strategies for NSCLC has notably enhanced patient prognosis, particularly through the advancements in molecular targeted therapy and immunotherapy (123). Recent studies indicate that the mortality rate of NSCLC has declined more significantly than its incidence rate in recent years, coinciding with the approval of targeted therapies (124). Currently, numerous targets and targetable pathways have been identified, including EGFR, ALK, RET, MET, PI3K/AKT/mTOR, RAS-MAPK, and NTRK/ROS1, among others (125, 126).

In this study, while the annual number of studies on apoptosis in NSCLC has consistently increased, the number of highly cited articles exhibits a fluctuating pattern and has demonstrated a negative growth trend over the past two decades. Upon reviewing the titles and abstracts of the 100 highly cited articles included in this analysis, they can be categorized into two main categories that articles are nearly equivalent in quantity. The first area of focus pertains to the mechanisms of apoptosis induced by pharmacological agents and compounds, as well as the mechanisms underlying drug resistance. Specifically, 17 articles address targeted therapies, primarily those involving EGFR-TKIs; 16 articles explore the effects of chemical compounds, including nicotine and curcumin; and 6 articles examine the role of chemotherapeutic agents. The other category pertains to the relationship between the expression of genes, proteins and other biomarkers and the process of apoptosis. Specifically, 17 articles focus on the involvement of related proteins in mediating apoptosis, 11 articles examine the direct or indirect role of microRNAs in regulating multiple apoptotic pathways, and 7 articles explore the regulation of apoptosis by long non-coding RNAs (lncRNA). The United States and China are identified as the first and second leading countries (regions) in terms of published articles ( Table 1 ). The United States holds the distinction of having the highest number of published articles, with a total of 60. Between 2004 and 2007, the United States contributed to over 80% of published articles. However, post-2008, there was a noticeable decline in the proportion of articles originating from the United States. The proportion of published articles originating from China has shown a continuous increase since 2013. Since that time, the annual number of highly cited articles from China has surpassed those from other countries. This trend underscores the significant contributions made by both the United States and China in this field. Regarding publishing institutions, the United States maintains a dominant position, with seven of the top 10 most productive institutions being based there, highlighting the critical role of the United States in this area of research.

The 100 articles analyzed were published in 45 distinct journals. Although none of these articles appeared in the top four medical journals, over 60% were published in journals with a high IF and were published in journals classified as JCR Q1, indicating that the field of NSCLC apoptosis research is well-established and has garnered significant attention from the academic community. Notably, some studies have been featured in prestigious scientific journals such as NATURE and SCIENCE. Additionally, publications have appeared in leading cell biology journals, including NATURE MEDICINE, CANCER CELL, NATURE CELL BIOLOGY, CELL DEATH AND DIFFERENTIATION. In this study, it was observed that the majority of articles with a higher number of citations were published in journals possessing a higher IF. However, journals with a greater number of co-citations did not necessarily exhibit a higher IF. Among the 45 journals analyzed, the lowest IF recorded was 1.6, demonstrating that even journals with a lower IF can produce highly cited articles. Furthermore, previous research has indicated that there is no statistically significant correlation between high citations counts and a journal’s IF (127). This finding underscores the importance of prioritizing the quality of individual papers alongside the journal IF.

Highly cited articles frequently represent the research focal points within a specific field, with keywords serving as significant indicators (128). Among the 100 articles analyzed, the most frequently occurring keyword is “expression”, followed by “activation”, “apoptosis”, “pathway and “gefitinib”. In the research articles examined, apoptosis is primarily induced through the regulation of the expression of microRNAs, tumor suppressors, EGFR, cell cycle proteins, and anti-apoptotic proteins, among others. Simultaneously, the study examined the activation of signaling pathways, transcription factors and various proteases involved in the regulation of apoptosis. The primary focus was on the activation of diverse signaling pathways and their impact on apoptosis. For instance, the activation of pathways such as PI3K/AKT, Wnt/β-catenin, and NF-κB by drugs or compounds plays a crucial role in modulating apoptosis in NSCLC. The findings indicate that the apoptosis pathway and the mechanisms by which drugs induce apoptosis remain among the most prominent topics of interest in the field.

Research priorities are subject to change over time. Consequently, a further examination and analysis of the top 10 most highly cited articles post-2021 revealed that the predominant keywords include “circular RNA”, “Nrf2”, “autophagy” and “ferroptosis”. This suggests that the regulation of circRNA and the targeting of the Nrf2 signaling pathway to induce apoptosis in NSCLC may constitute a significant focus of contemporary research. The dysregulated expression and control of circRNA are recognized as playing a crucial regulatory role in NSCLC (129). Two of the studies included in the analysis have demonstrated that silencing tumor-derived exosomal circRNA_102481 can enhance apoptosis in EGFR-TKIs resistant NSCLC, while the loss of circRNA vacuolar membrane protein 1 similarly promotes apoptosis of cisplatin-resistant NSCLC (129, 130). Additionally, one of the articles reported that kaempferol effectively induces down-regulation of Nrf2 mRNA and disrupts Nrf2 downstream signaling in a redox-independent manner, thereby facilitating apoptosis in NSCLC (131). Four articles have concurrently examined ferroptosis and apoptosis, as well as the interplay between autophagy and apoptosis, thereby analyzing the relationship and interactions between the processes. This research has significantly enhanced the understanding of cell death mechanisms (132–135).

The principal mechanisms of cancer cell death encompass apoptosis, pyroptosis, autophagy and necrosis, with apoptosis being particularly significant (136). Apoptosis is characterized as a gene-regulated, programmed cell death process that maintains cellular homeostasis without eliciting an inflammatory response. It can be initiated via an extrinsic pathway, triggered by cell surface death receptors, or an intrinsic pathway, primarily activated by mitochondrial damage. Both pathways predominantly involve the mediation of effector caspases (137–139). The canonical mechanism of apoptosis involves the activation of the caspase pathway. Initiator caspases, including caspase-2, -8, and -9, play a critical role in triggering the apoptotic cascade by activating downstream effector caspases, such as caspase-3, -6, and -7, which ultimately execute the apoptotic process (140–142). The exogenous apoptotic pathway is activated by various death receptor stimuli, including Fas, tumor necrosis factor (TNF) receptors, and the TNF-related apoptosis-inducing ligand receptor (TRAILR), among others. These membrane receptors, which participate in the apoptotic process, are members of the TNF receptor superfamily. Within this family, TNF and Fas serve as the primary ligands that activate these receptors, thereby initiating the TNF signaling pathway (143, 144). Endogenous apoptotic pathways are activated by factors such as DNA damage, energy deprivation, and hypoxia, leading to the dephosphorylation and cleavage of pro-apoptotic proteins, their translocation to the mitochondria, and the subsequent induction of apoptosis (143). Additionally, the endoplasmic reticulum (ER) plays a critical role in apoptosis. Dysfunction in protein folding within the ER results in the accumulation of unfolded or misfolded proteins in its lumen, thereby inducing ER stress and contributing to the apoptotic process (145).

Numerous signaling pathways are implicated in the regulation of apoptosis in NSCLC, including but not limited to STAT3, Wnt/β-catenin, NF-κB, PI3K/AKT, mTOR, MAPK/Slug, ROS, p53, and Nrf2. These pathways can modulate apoptosis through both endogenous and exogenous mechanisms (146). Additionally, a range of pro-apoptotic regulatory factors are involved this process, including cytochrome C, Smac/DIABLO, Omi/HtrA2, AIF, and endonuclease G, among others (147). Numerous genes and proteins play crucial roles in the mechanism of apoptosis. For instance, TP53 is a significant tumor suppressor gene that can arrest the cell cycle and promote apoptosis. P53, a widely studied pro-apoptotic transcription factor, is a key participant in the cell cycle regulation. Apoptosis signal induced by cancer cells is p53-dependent (148, 149). For instance, the BCL-2 protein family plays a crucial role in the regulation of apoptosis and is categorized into three distinct subgroups: anti-apoptotic proteins (including BCL-2, BCL-xL, BCL-w, MCL-1, and BFL-1), multi-BH domain pro-apoptotic proteins (such as BAK, BAX, and BOK), and BH3-domain only pro-apoptotic proteins (such as BIM, BAD, BID, NOXA, BIK, HRK, BMF and PUMA) (150, 151). Venetoclax, the sole globally approved Bcl-2 selective inhibitor, has received approval for the treatment of relapsed or refractory chronic lymphocytic leukemia and acute myeloid leukemia in elderly patients. However, its clinical indications for other diseases remain under investigation (152).

Consequently, targeting the apoptotic pathway represents a potent strategy for the treatment of NSCLC. Anticancer agents exert their effects by inducing apoptosis and arresting the cell cycle (153). These agents facilitate apoptosis by inhibiting the expression of anti-apoptotic proteins, upregulating pro-apoptotic proteins, decreasing mitochondrial membrane potential, and promoting the release of cytochrome C (154, 155). Mutations in EGFR, human epidermal growth factor receptor-2 (HER-2), or Kirsten rat sarcoma virus oncogene homolog (KRAS) result in increased tumor cell proliferation and diminished apoptosis (156). A critical mechanism by which EGFR-TKIs exert therapeutic effects in EGFR-mutated NSCLC is through the induction of apoptosis. This process is mediated by the regulation of BCL-2 family protein expression, with the pro-apoptotic protein BIM plays a pivotal role (157, 158). Nevertheless, drug resistance in patients with NSCLC patients with NSCLC remains a significant challenge. Drug resistance can be categorized into primary and acquired types. Primary drug resistance is present in a minor subset of cancer cells that have not previously undergone treatment, whereas acquired drug resistance frequently proves difficult to circumvent (159). The mechanisms underlying drug resistance in LC are predominantly associated with gene mutations, gene deletions, gene amplifications, pharmacokinetics factors, targeting of oncogenes, and drug-induced apoptosis (160, 161). Inhibition of apoptosis represents a principal factor contributing to multidrug resistance in tumors, with the PI3K/AKT signaling pathway playing a crucial role in the regulation of this resistance in cancer (162). Residual cancer cells that persist following drug treatment can act as reservoirs for acquired drug resistance. Therefore, augmenting initial drug-induced apoptosis and minimizing residual lesions is a promising strategy to mitigate drug resistance (65). Currently, research on EGFR-TKI has progressed to the fourth generation, with compounds such as EAI045, OBX02-011, LS-106 and CH7233163 under investigation. These fourth-generation drugs are anticipated to address multiple mechanisms of drug resistance, including those associated with third-generation inhibitors, which are predominantly exemplified by resistance to osimertinib (163). Inhibition of apoptosis has implications for tumor drug resistance. In the context of hematological malignancies, the use of BCL-2 family inhibitors in combination therapies has been shown to effectively enhance apoptosis and diminish drug resistance (164, 165). A Phase I clinical trial investigating the combination of osimertinib and ABT-263 (Navitoclax) for the treatment of LC patients with EGFR mutations, following the failure of EGFR-TKI therapy, utilized a dosage regimen of 80 mg/day of osimertinib and 150 mg/day of Navitoclax. The treatment was both efficacious and well-tolerated by the patient cohort (164). A study has demonstrated that the upregulation of BCL2L1 expression constitutes the primary alteration observed in cells that develop resistance to EGFR-TKI (166).

LncRNAs constitute a significant focus within the literature reviewed in this study. These molecules are intricately associated with the pathogenesis of NSCLC and are critical in modulating drug resistance mechanisms. Evidence indicates that lncRNAs contribute to the development of cisplatin resistance in LC, potentially influencing resistance to taxanes and acquired resistance to EGFR-TKIs (167). The lncRNA/PTEN axis is pivotal in modulating the sensitivity of LC cells to chemotherapeutic agents. Research indicates that miRNA-221 contributes to the development of cisplatin resistance in LC by down-regulating PTEN (168). The suppression of LINC01296 has been shown to significantly enhance the sensitivity of NSCLC to paclitaxel (169). LncRNAs play a crucial role in the emergence and progression of resistance to EGFR-TKIs in NSCLC by modulating various molecular pathways. Certain lncRNAs enhance the expression of oncogenes, thereby facilitating tumor cell proliferation, survival, and resistance to EGFR-TKI. Additionally, some lncRNAs suppress the expression of tumor suppressor genes, induce the epithelial-mesenchymal transition (EMT) process, and ultimately contribute to EGFR-TKI resistance. This resistance is partially mediated through the activation of the Rho-associated protein kinase (ROCK) and mesenchymal-epithelial transition factor (MET) signaling pathways. Certain lncRNAs suppress the expression of tumor suppressor genes and induce the EMT process, ultimately contributing to resistance against EGFR-TKIs. This resistance is partially mediated through the activation of the ROCK and MET signaling pathways (170). CircRNAs represent a novel category of endogenous ncRNAs characterized by a covalently closed-loop structure. Currently, substantial evidence suggests that circRNAs are capable of modulating gene expression across various levels. These regulatory functions include influencing the transcription of their parental genes, affecting the splicing processes of their linear counterparts, serving as microRNA sponges, modulating the activity of RNA-binding proteins, and facilitating the encoding of peptides (171). Aberrant circRNAs play a significant role in various developmental processes of malignant tumors, such as tumorigenesis, growth, metastasis, apoptosis, angiogenesis, and resistance to chemotherapy (172). CircRNAs have been identified as crucial elements within the intricate regulatory network of the KRAS pathway across different cancer types. Investigating the involvement of circRNAs in the KRAS pathway could enhance strategies for cancer detection and treatment (173). Currently, numerous studies have identified that certain circRNAs are down-regulated in tumors, potentially contributing to the inhibition of tumor chemotherapy resistance. Conversely, their up-regulation may enhance chemotherapy resistance (174). These circRNAs can modulate the resistance of various tumors to conventional chemotherapy or immunotherapy, either positively or negatively (172). Consequently, circRNAs hold promise as potential diagnostic, prognostic, and therapeutic targets for cancer. Furthermore, they offer a promising avenue for research aimed at addressing the challenge of drug resistance in LC. Nrf2 is a pivotal transcription factor that plays an essential role in the oxidative stress response. It possesses the capacity to modulate apoptosis in human cancer cells, exhibiting a dualistic function. The interaction between Nrf2 and apoptosis processes can significantly influence cancer progression (175). The accumulation of Nrf2 within cancer cells, along with its cytoprotective effects, can be attributed to somatic mutations in Nrf2, Keap1, or CUL3. Additionally, the down-regulation of Keap1, as well as the interactions of p62/Sqstm1 and p21 with Keap1, can impact Nrf2 levels (176). Mutations within the Keap1/Nrf2 signaling pathway have been implicated in the development of resistance to cancer chemotherapy, targeted therapies, and radiotherapy (177). Yoon Jin Lee. et al. (2020) (178) demonstrated that Nrf2 can enhance the survival rate of cancer cells by inhibiting apoptosis. The overexpression of Nrf2 may be associated with tumorigenesis and tumor progression. In cancer cells, the overexpression of NRF2, resulting from constitutive activation or hyperactivation, facilitates their survival in environments rich in ROS, which is closely associated with enhanced proliferation and increased resistance to chemotherapy (179). Currently, research on NRF2 activators is extensive, whereas investigations into NRF2 inhibitors remain limited (180). NRF2 represents a promising therapeutic target or a potential avenue for targeted therapy, given the frequent occurrence of molecular pathway disruptions or loss-of-function mutations in tumors.

According to the search, no bibliometric study on the same topic as this study was found. This study utilized the WOSCC, recognized as a relatively authoritative citation database (181). Through an analysis of the 100 most highly cited articles, the study identified the most influential countries (regions), institutions, journals and authors in the field of NSCLC apoptosis. Using bibliometric methods, the research summarized the current status and key areas of interest within this field and projected future research trends based on the temporal distribution of keywords.

Apoptosis-based therapeutic strategies have undergone extensive development over the years. Currently, significant advancements have been achieved in the formulation of novel pharmacological agents and in addressing the challenge of existing drug resistance. Despite the absence of approved anti-apoptotic drugs specifically for NSCLC, these therapies hold considerable potential for future applications. The resistance to anti-tumor drugs remains a formidable challenge within oncology, with the suppression of apoptosis identified as a principal factor contributing to the multidrug resistance observed in tumors. LncRNAs, circRNAs and Nrf2 represent promising therapeutic targets and strategies for addressing cancer drug resistance. The advancement of drugs targeting these molecules holds significant clinical value. Nonetheless, the development of Nrf2 inhibitors aimed at overcoming tumor multidrug resistance remains in its nascent stages, with limited research conducted on these inhibitors to date. NcRNAs have been demonstrated to play a critical role in the development of drug resistance across various therapeutic modalities, including chemotherapy, targeted therapy, immunotherapy, and others, with particular emphasis on lncRNAs and circRNAs. Modulating dysregulated ncRNAs presents a promising therapeutic strategy to counteract drug resistance. Continued investigation into their regulatory mechanisms in anti-tumor drug resistance is essential for advancing the treatment of NSCLC. Consequently, it is anticipated that this area will become a focal point of future research endeavors. Despite these advancements, significant challenges remain in the development of novel pharmacological agents and in overcoming resistance to existing treatments. Consequently, additional research is unequivocally warranted to advance future developments. It is anticipated that such efforts will yield significant breakthroughs in the diagnosis, treatment, and mitigation of drug resistance in cancer.

Nevertheless, this study is subject to certain limitations: (1) The analysis was conducted using the WOSCC, yet numerous other databases, such as PubMed and Scopus, exist. The citation counts of articles vary across these databases (182), potentially affecting the study’s analytical outcomes based on the database selection. (2) Articles of significant influence may not have accrued sufficient citations to be included in the top 100 due to their recent publication, potentially omitting emerging research trends from the study. (3) The citation count of an article can be influenced by various factors, including the prestige of the publishing journal and the incidence of self-citation, among others. Consequently, while citation count serves as a significant metric for assessing an article’s impact, it should not be considered the sole indicator. (4) Furthermore, this study exclusively included English-language articles from the WOSCC, which may result in the exclusion of potentially influential articles published in other languages.