Apoptosis signaling and cancer targeted therapy: from bench to bespoke

Introduction

Cancer remains a significant disease burden worldwide, with incidence and mortality continuing to rise (1). Apoptosis is a programmed cell death process essential for tissue homeostasis and the removal of damaged or harmful cells (2). Normally, apoptosis acts as a protective barrier by eliminating potentially malignant cells. However, cancer cells frequently acquire the ability to circumvent apoptotic signaling, promoting tumor progression, metastasis, and resistance to therapy. Consequently, dysregulated apoptosis not only facilitates malignant transformation but also undermines the efficacy of conventional treatments (3).

Evading apoptosis is a well-established hallmark of cancer (4). Accordingly, therapeutic strategies aimed at reactivating apoptotic pathways in cancer cells have garnered significant interest (5,6). Among these, BH3 mimetics (7) represent the most clinically mature class, whereas p53-reactivating agents, second mitochondria-derived activator of caspases (SMAC) mimetics (8), death receptor agonists, and direct caspase activators remain at earlier stages of development. Furthermore, there is growing interest in integrating apoptosis-targeted agents with conventional treatments. These combination regimens aim to overcome resistance mechanisms, enhance therapeutic efficacy, and improve clinical outcomes.

This review provides a comprehensive overview of the molecular mechanisms governing apoptosis. It emphasizes how apoptosis dysregulation contributes to tumorigenesis and therapeutic resistance. We first summarize the basic biology of apoptosis, then discuss major mechanisms of apoptotic dysregulation in cancer, followed by therapeutic strategies, emerging platforms, and key translational challenges.

Overview of apoptosis

Apoptosis, a programmed cell death process distinct from necrosis, was first described in 1972 by John Kerr and colleagues based on its unique morphological characteristics (9). Nearly two decades later, the first apoptosis-related gene, ced-9, was identified in studies of the nematode Caenorhabditis elegans (10). BCL-2 is the human homolog of ced-9 and plays a pivotal role in regulating apoptosis (11). Later research uncovered many apoptotic regulators and elucidated their molecular mechanisms (12).

Building on these discoveries, it is clear that apoptosis plays a crucial role in maintaining cellular homeostasis and contributes to various physiological processes, particularly cell turnover in adult tissues (13). It can be triggered under physiological or pathological conditions in response to intracellular stress, toxic insults, or anticancer therapies. It also plays a key role in treatment-induced tumor regression (4).

Apoptotic signaling proceeds primarily through two interconnected pathways: the intrinsic pathway, activated by intracellular stress and controlled by the BCL-2 family proteins, and the extrinsic pathway, triggered by ligand engagement of cell-surface death receptors (Figure 1). Both pathways converge on a conserved family of cysteine proteases called caspases. Specifically, initiator caspases include caspase-9 for the intrinsic pathway and caspase-8/caspase-10 for the extrinsic pathway. They activate downstream effector caspases, such as caspase-3, caspase-6, and caspase-7. These effector caspases work collaboratively to dismantle structural and regulatory proteins, leading to the fragmentation of the cell into apoptotic bodies.

Figure 1 Crosstalk between extrinsic and intrinsic apoptotic pathways. Created using BioRender. Death receptor ligation promotes DISC assembly and caspase-8 activation, which either directly activates effector caspases or cleaves BID to connect with mitochondrial apoptosis. Intrinsic stress signals activate BAX/BAK-dependent MOMP, releasing cytochrome c to form the apoptosome and SMAC (DIABLO) or HtrA2 to relieve IAP-mediated caspase suppression; both routes converge on caspase-3/7 activation. AIF, apoptosis-inducing factor; APAF-1, apoptotic protease-activating factor-1; DISC, death-inducing signaling complex; FADD, Fas-associated death domain; IAP, inhibitor of apoptosis protein; MOMP, mitochondrial outer membrane permeabilization; SMAC, second mitochondria-derived activator of caspases; tBID, truncated BID.

Intrinsic apoptotic pathway

The intrinsic pathway, also known as the mitochondrial apoptotic pathway, is typically triggered by intracellular stressors, including DNA damage, oxidative stress, withdrawal of growth factors, and hypoxia. This pathway is tightly regulated by the BCL-2 protein family (14), whose members can be functionally grouped into three subgroups: anti-apoptotic proteins, pro-apoptotic effectors (BAX, BAK), and pro-apoptotic BH3-only proteins that act as either activators or sensitizers.

Under normal physiological conditions, BAX and BAK remain inactive in the cytosol or mitochondrial outer membrane (MOM). Upon apoptotic stimulation, BH3-only proteins become activated via transcriptional upregulation, post-translational modifications (PTMs), or proteolytic cleavage. Activator BH3-only proteins then bind directly to BAX or BAK, inducing conformational changes and oligomerization at the MOM that drive MOM permeabilization (MOMP), a defining event of intrinsic apoptosis. However, this activation is antagonized by anti-apoptotic BCL-2 family proteins, which sequester activator BH3-only proteins or BAX/BAK intermediates to prevent MOMP (15). Instead of directly activating BAX or BAK, sensitizer BH3-only proteins overcome this blockade by binding to and neutralizing the anti-apoptotic BCL-2 proteins. This action releases activator BH3-only proteins or partially activated BAX/BAK, allowing pore formation at the MOM. Through this displacement mechanism, sensitizers amplify pro-apoptotic signaling and lower the threshold required for MOMP.

Following MOMP, intermembrane space proteins, most notably cytochrome c (16), SMAC (DIABLO), and HtrA2 (Omi), are released into the cytosol. In the cytosol, cytochrome c binds to apoptotic protease-activating factor-1 (APAF-1), driving formation of the apoptosome. This complex then recruits and activates initiator caspase-9. Activated caspase-9 subsequently cleaves and activates effector caspases, including caspase-3 and caspase-7, thereby initiating the proteolytic cascade that irreversibly dismantles cells (17). At the same time, SMAC and HtrA2 antagonize inhibitor of apoptosis proteins (IAPs), thereby relieving caspase inhibition (18,19).

Extrinsic apoptotic pathway

The extrinsic apoptotic pathway is initiated when extracellular death ligands bind to specific death receptors on the cell surface (20). Key ligand-receptor pairs include Fas ligand (FASL) with Fas, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) with TRAIL receptor 1 and 2 (DR4/DR5), and TNF with TNF receptor 1 (TNFR1) (14,21,22).

Ligand binding promotes assembly of the death-inducing signaling complex (DISC), which typically contains the receptor, the adaptor Fas-associated death domain (FADD), and procaspase-8 or procaspase-10. Dimerization and processing of procaspase-8 initiate downstream caspase activation. In type I cells, this input is sufficient to activate effector caspases directly. In type II cells, the signal requires mitochondrial amplification: caspase-8 cleaves BID to truncated BID (tBID), which activates BAX/BAK and engages the intrinsic pathway (20,23).

In addition to caspase activation, death receptor engagement can also activate survival signaling, particularly through the TNFR1 axis. Cellular IAP1 (cIAP1) and cellular IAP2 (cIAP2) help regulate receptor-proximal signaling and can promote nuclear factor-κB (NF-κB)-mediated transcription of anti-apoptotic genes, thereby counteracting apoptotic signaling and supporting tumor cell survival (24,25). This context dependence helps explain why death receptor ligands do not uniformly trigger apoptosis.

Accordingly, the extrinsic pathway is best understood as a context-dependent signaling hub. Its pro-apoptotic output depends on efficient DISC formation and, in many cells, productive crosstalk with mitochondrial apoptosis through tBID.

Mechanisms of apoptotic dysregulation in cancer

Apoptosis is a physiological process that eliminates unwanted or damaged cells. In healthy tissues, pro- and anti-apoptotic factors work in close coordination to regulate normal cell turnover. In cancer, however, apoptosis is suppressed through multiple molecular mechanisms, ultimately contributing to uncontrolled tumor growth and drug resistance. Understanding these mechanisms provides important insight for the development of targeted therapies.

p53 signaling and apoptosis

The p53 protein is a pivotal tumor suppressor that maintains genomic stability and regulates cell-cycle arrest, DNA repair, and apoptosis (26). p53 exists as a mixture of monomers, dimers, and tetramers, with dimers being the predominant form under physiological conditions. Its expression is maintained at low levels through constant ubiquitin-mediated proteasomal degradation, primarily driven by its negative regulator MDM2, an E3 ubiquitin ligase (27).

Among various types of cellular stress, DNA damage is one of the most potent activators of p53. When genotoxic stress occurs, checkpoint kinases such as CHK2 phosphorylate p53 and disrupt its interaction with MDM2, thereby preventing ubiquitin-mediated degradation. Acetylation and other PTMs further enhance p53 stability and transcriptional activity. When DNA damage can be repaired, p53 upregulates cell-cycle inhibitors such as p21 and DNA repair genes, including GADD45 and P53R2, thereby limiting mutational burden (28-30). However, if DNA damage is irreparable, p53 shifts toward apoptosis. It transcriptionally upregulates pro-apoptotic BCL-2 family members, particularly BH3-only proteins such as PUMA and NOXA, and, in some contexts, BAX. These proteins promote MOMP, cytochrome c release, apoptosome formation, and caspase activation (31). Beyond its transcription-dependent roles, p53 can also translocate to the mitochondria and interact with BCL-2 family proteins to facilitate MOMP. This mitochondrial role should be distinguished from direct canonical opening of the mitochondrial permeability transition pore, which is not generally regarded as the main mechanism of p53-induced apoptosis in cancer models (32).

Loss of p53 function is reported in about 50% of human tumors, most commonly through inactivating TP53 mutations, which abolish its DNA-binding capacity and transcriptional activation of pro-apoptotic genes. Some mutations clustered in the DNA-binding domain may even confer oncogenic gain-of-function properties. In contrast, certain tumors retain wild-type TP53 but experience functional silencing due to upstream alterations. For instance, MDM2 overexpression accelerates p53 ubiquitination and degradation, while inactivation of ARF may occur through deletion or promoter hypermethylation (33,34). In addition, oncogenic pathways such as PI3K/AKT and MAPK can enhance MDM2 activity or expression, thereby further suppressing p53. These alterations lower both p53 levels and activity, effectively mimicking TP53 mutation and allowing tumor cells to evade apoptosis despite retaining an intact TP53 coding sequence.

These findings support at least two therapeutic directions: restoring wild-type p53 when it is functionally suppressed and reactivating or bypassing mutant p53 in TP53-altered tumors.

BCL-2 family proteins and mitochondrial priming

The BCL-2 family plays a central role in regulating intrinsic apoptosis and is essential for the balance between cell survival and programmed cell death (2). BCL-2, first identified by Tsujimoto et al. in 1984, is one of the most extensively studied proto-oncogenes in apoptosis (35). In 1988, Vaux and colleagues discovered that BCL-2 possesses anti-apoptotic activity, a landmark finding that has set the direction of BCL-2 research in recent decades (36). Afterwards, numerous BCL-2 family members were identified, all of them sharing at least one BCL-2 homology (BH) domain. Based on their domain composition and functional roles, BCL-2 family proteins can be categorized into three distinct groups. (I) Anti-apoptotic proteins (e.g., BCL-2, BCL-XL, BCL-W, MCL-1, BFL-1) contain all four BH domains (BH1–4). They prevent apoptosis by sequestering pro-apoptotic factors and preserving mitochondrial integrity. (II) Pro-apoptotic effectors (e.g., BAX, BAK) also possess BH1–4 domains. They directly promote apoptosis by oligomerizing at the MOM to form proteolipid pores that mediate MOMP (37). (III) BH3-only proteins act as sentinels of cellular stress and initiate apoptosis. BH3-only proteins can be further divided into activators (e.g., BID, BIM, PUMA) that directly oligomerize BAX/BAK to trigger MOMP, and sensitizers (e.g., BAD, NOXA, BMF) that bind and neutralize anti-apoptotic members, thereby liberating activators or partially activated BAX/BAK (11).

In cancer, apoptosis resistance often reflects a shift toward anti-apoptotic dependence. Overexpression of BCL-2, BCL-XL, or MCL-1 raises the threshold for MOMP, blunts cytochrome c and SMAC release, and contributes to disease progression, poor prognosis, and treatment resistance (38). This concept of apoptotic priming is therapeutically relevant because tumors that remain highly dependent on one dominant anti-apoptotic protein are often especially vulnerable to BH3 mimetics, whereas tumors able to switch dependency to MCL-1 or BCL-XL more readily escape treatment pressure.

Caspase signaling and execution failure

Caspases are cysteine proteases that execute apoptosis once upstream checkpoints are breached. Initiator caspases, including caspase-8, caspase-9, and caspase-10, are activated within signaling platforms such as the DISC or apoptosome, whereas effector caspases, including caspase-3, caspase-6, and caspase-7, dismantle the cell by cleaving structural, repair, and signaling proteins (17,39-41).

Given the central role of caspases in apoptosis, their inactivation can profoundly alter cell fate. In cancer, caspase inactivation is a key mechanism by which tumor cells evade apoptosis. This inactivation may result from overexpression of anti-apoptotic proteins, downregulation of pro-apoptotic proteins, or mutations that directly impair caspase function (42). Loss of caspase function not only promotes the survival of damaged or genetically unstable cells, contributing to genomic instability and malignant transformation (43), but also undermines the efficacy of apoptosis-dependent therapies (44). Many anticancer agents, including chemotherapies and targeted therapies, exert their effects by activating apoptotic pathways. Without functional caspase activity, tumor cells evade drug-induced apoptosis. Apart from conferring resistance to therapy, caspase inactivation also hampers antitumor immunity by disrupting apoptosis-associated immune signaling (45,46).

In brief, caspase inactivation provides tumor cells with a dual advantage: resistance to apoptosis and evasion of immune surveillance, thereby promoting tumor persistence and progression. Although restoring caspase activity is conceptually attractive, direct pharmacologic activation remains challenging because of potential toxicity in normal tissues. More realistic therapeutic strategies often aim to restore upstream apoptotic signaling rather than indiscriminately activate effector caspases.

IAPs and survival signaling

The IAP family comprises a group of highly conserved endogenous proteins that suppress apoptosis and are frequently dysregulated in cancer (47). Since their initial discovery in baculoviruses in 1993 (48), eight IAP members have been identified in mammals, including cIAP1, cIAP2, XIAP, survivin (BIRC5), BRUCE, and livin (49). These proteins inhibit apoptosis through several mechanisms. XIAP is the family member most directly responsible for caspase inhibition, binding caspase-3, caspase-7, and caspase-9; this inhibition can be antagonized by SMAC, thereby restoring caspase activity (50,51). Survivin is also highly expressed in various tumors and contributes to both apoptosis resistance and cell-cycle regulation (52,53). By contrast, cIAP1 and cIAP2 are better understood as E3 ubiquitin ligases and signaling scaffolds that regulate TNFR1/RIPK1/NF-κB signaling, thereby promoting cell survival rather than acting as the main direct caspase inhibitors (54,55).

Mitochondrial and metabolic alterations relevant to apoptosis

Mitochondria not only produce energy but also regulate programmed cell death (56). Alterations in mitochondrial DNA (mtDNA), tricarboxylic-acid-cycle enzymes, and mitochondrial metabolism can reshape apoptotic sensitivity through effects on redox homeostasis, ATP production, and stress signaling (56-59). For this reason, this topic is better framed as mitochondrial and metabolic alterations relevant to apoptosis rather than a single mitochondrial mutation pathway. Importantly, the therapeutic maturity of this area is uneven: mutant IDH inhibition has clinical relevance in selected cancers, whereas mitochondrial transplantation and mtDNA correction remain highly exploratory.

Therapeutic strategies to restore apoptosis

Because the clinical maturity of apoptosis-targeted strategies differs substantially, it is useful to distinguish clinically validated or late-stage approaches from early clinical and exploratory strategies. In the sections below, BH3 mimetics are discussed as the most mature class, whereas p53-directed therapies, caspase/TRAIL-based approaches, and IAP antagonists remain largely early clinical or investigational. More exploratory metabolism-directed, RNA-based, and genome-engineering approaches are discussed separately. Table 1 and Figure 2 summarize this hierarchy.

Figure 2 Evidence hierarchy and translational barriers in apoptosis-targeted cancer therapy. The schematic groups apoptosis-targeted strategies into clinically validated or late-stage approaches, early clinical approaches, and exploratory/preclinical platforms, and highlights shared translational barriers including biomarker selection, on-target toxicity, adaptive resistance, and delivery constraints. IAP, inhibitor of apoptosis protein; mRNA, messenger RNA; mtDNA, mitochondrial DNA; SMAC, second mitochondria-derived activator of caspases; TRAILR, tumor necrosis factor-related apoptosis-inducing ligand receptor.

Early clinical strategies targeting the p53 pathway

Given that p53 inactivation occurs via direct mutation or upstream dysregulation in over half of human cancers, diverse strategies have been developed to restore or enhance p53 activity (74,75). In TP53-wild-type tumors with functional suppression, the principal therapeutic approach is to disrupt negative regulation by MDM2 (76). Nutlin-3 was the first compound identified in this class, and derivatives such as RG7112 and RG7388 (idasanutlin) have entered clinical evaluation (74,75,77-79). Idasanutlin combined with cytarabine improved overall response rate in acute myeloid leukemia but failed to improve overall survival, and hematologic and gastrointestinal toxicities remain important limitations (78,79). Other MDM2 inhibitors, such as APG-115, AMG 232/KRT-232, and dual MDM2/MDMX inhibitors, further support the therapeutic relevance of this axis (80). Because PI3K/AKT and MAPK signaling can enhance MDM2 activity, these pathways may also represent indirect ways to restore p53 signaling in selected tumors.

In tumors harboring TP53 mutations, efforts focus on restoring wild-type-like conformation or function of mutant p53. Compounds in this area include PRIMA-1 derivatives such as APR-246 (eprenetapopt), arsenic trioxide, mutation-specific ligands, aggregation-disrupting agents, degradation strategies, and p53 replacement approaches (26,74,75,81-92). These strategies remain scientifically important, but their translational maturity is generally earlier than that of BH3 mimetics, and their activity is often mutation-context dependent. For nonsense mutations or TP53 loss, gene or mRNA delivery, translational readthrough, and oncolytic virotherapy remain largely preclinical.

Clinically validated and developing BCL-2-targeted strategies

Overexpression of BCL-2 in various tumor types makes it an attractive therapeutic target (93). Among apoptosis-targeted therapies, BH3 mimetics are the most clinically mature class. Early agents such as obatoclax and ABT-737 established proof of concept, whereas navitoclax (ABT-263) and venetoclax (ABT-199) demonstrated clearer translational potential (94-100). Navitoclax showed promising antitumor activity but was limited by dose-limiting thrombocytopenia caused by BCL-XL inhibition (98,99). Venetoclax was designed to selectively target BCL-2 while sparing BCL-XL and has become the most clinically advanced apoptosis-directed therapy, particularly in hematologic malignancies (64,100). Nucleic acid-based strategies such as RNA interference (RNAi) or antisense oligonucleotides against BCL-2 remain less mature and still require further evaluation (101).

Despite the therapeutic opportunity offered by venetoclax, heterogeneity of response and acquired resistance remain major challenges in acute myeloid leukemia and related settings (102-104). Reported mechanisms include switching dependence to MCL-1 or BCL-XL, mutations or dysfunction of TP53 and BAX, activation of pro-survival signaling pathways, mitochondrial metabolic reprogramming, and protective cues from the bone marrow microenvironment (102-104). These resistance mechanisms are directly relevant to future strategies discussed later in this review, including mechanism-based combinations, mRNA replacement of lost apoptotic effectors, and genome-editing approaches for genetically defined lesions.

Early clinical strategies targeting caspase, death receptors, and IAPs

Given their pivotal role in apoptosis, caspases and death-receptor pathways remain attractive but challenging therapeutic targets. Approaches such as PIDDosome-associated caspase-2 activation, procaspase activators, and TRAIL-receptor agonists have shown mechanistic promise (105-109). However, direct caspase activation remains difficult because the therapeutic window may be narrow, and death-receptor agonists have shown only modest single-agent activity in many clinical settings. Recombinant Apo2L (rhApo2L) corresponds to recombinant human TRAIL rather than a precursor of TRAIL. Overall, caspase- and TRAIL-based strategies are better viewed as early clinical or combination-oriented approaches than as established standalone therapies.

IAPs have also emerged as attractive targets in cancer, especially through the development of SMAC mimetics (50,110,111). Agents such as LCL161, xevinapant, birinapant, and APG-1387 can relieve IAP-mediated apoptosis resistance and may be particularly useful in combination regimens (112-120). However, clinical activity has been variable, and toxicities or inflammatory context dependence remain important limitations. Xevinapant is among the more encouraging examples, whereas other SMAC mimetics have shown more mixed efficacy. Accordingly, IAP-targeted therapy remains promising but not yet clinically consolidated.

Exploratory metabolism-directed strategies with apoptosis relevance

Therapeutic strategies related to mitochondrial mutation or mitochondrial restoration should be discussed more cautiously. Nanoparticle-mediated gene correction, delivery of wild-type mtDNA, and transplantation of healthy mitochondria are conceptually interesting but remain highly exploratory in cancer (121-123). By contrast, metabolism-directed agents such as mutant IDH inhibitors have clearer clinical relevance, although their connection to apoptosis is indirect rather than a direct engagement of the core apoptotic machinery. This distinction helps separate exploratory concepts from more established therapeutic approaches.

Experimental and emerging strategies

Emerging therapeutic strategies, such as RNAi, mRNA therapy, bispecific antibodies, and gene-editing technologies, provide additional opportunities to modulate apoptosis in cancer treatment. For patients with low or defective levels of pro-apoptotic proteins, mRNA therapies that deliver mRNA into tumor cells to restore protein expression may be a viable option (124). Similarly, RNAi-mediated silencing of anti-apoptotic proteins overexpressed in tumor cells, achieved by delivering antisense oligonucleotides or small interfering RNAs, may help trigger apoptosis in cancer cells. Advances in adeno-associated virus (AAV) and nanoparticle technologies may enhance the development of gene therapy, although the efficiency and specificity of nucleic acid delivery remain critical challenges (125).

The identification of tumor-specific antigens related to apoptosis pathways also supports the development of bispecific antibodies, cell therapies, and p53-targeted vaccines (126-129). In addition, correction of genetic lesions by CRISPR-Cas9-based editing has considerable long-term potential as a novel apoptosis-relevant therapeutic strategy (129,130). At present, however, these platforms should be regarded as experimental. Their near-term value may be greatest as biomarker-guided or combination-based approaches rather than immediate replacements for clinically established agents (131-133).

Key translational challenges

A more critical appraisal of translational limitations is essential. Several apoptosis-targeted strategies have shown biologic or early clinical activity, but on-target toxicity remains a recurrent barrier. Examples include the lack of overall survival benefit and treatment-related toxicities observed with idasanutlin, as well as navitoclax-associated thrombocytopenia (78,79,98,99). These findings indicate that even mechanistically compelling agents may fail clinically if safety and patient selection are not adequately addressed.

Adaptive resistance is another major challenge. Tumors can evade apoptosis by shifting dependence among BCL-2 family proteins, acquiring alterations in TP53 or BAX, rewiring mitochondrial metabolism, or exploiting protective microenvironmental signals (102-104). These mechanisms underscore the need for mechanism-based combination therapies rather than reliance on single agents alone.

Finally, biomarker selection and drug delivery remain underdeveloped across much of the field. Many agents are unlikely to succeed without better matching to tumor genotype, pathway dependence, and microenvironmental context. These issues are especially important for RNA- and gene-based strategies, where efficient and tumor-selective delivery is still a central obstacle (124,125,129,133).

Conclusions

Over the past decades, research into the molecular mechanisms of apoptosis has profoundly reshaped our understanding of tumor biology and treatment resistance. These advances have already yielded multiple targeted strategies that work by restoring apoptotic competence in cancer cells, with BH3 mimetics providing the clearest clinical proof of concept. By contrast, p53 reactivators, IAP antagonists, death receptor agonists, and direct caspase-targeted approaches remain at earlier stages of development, while RNA-based and genome-editing approaches are still largely experimental.

Further progress will depend on continued mechanistic insight, stronger biomarker-guided patient selection, rational combination strategies, and more effective delivery platforms. With sustained translational research, targeting the molecular machinery of apoptosis may become an increasingly important component of precision cancer therapy.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0243/prf

Funding: This work was supported by the National Natural Science Foundation of China (Nos. 82273418 and 82273380) and the Shanghai Rising-Star Program (No. 23QA1407900).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0243/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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