Smoking and the circuits that maintain addiction

Quitting smoking is often described as a sudden, almost symbolic gesture: the last cigarette, the pack thrown away, the beginning of a new phase. From a biological perspective, however, cessation is not merely a psychological event, but the interruption of a continuous toxic pressure that has altered the functioning of the entire organism for years. It is like gradually extinguishing a slow but steady fire: the existing damage does not disappear immediately, but the body finally stops being subjected to new assaults and can slowly begin a recovery process.

One of the most extraordinary aspects to emerge from modern scientific research is the speed at which biological risk begins to decrease after cessation. For many years, it was thought that the benefits of quitting smoking would only become evident after decades. Recent evidence, however, shows that recovery begins much sooner, especially in terms of cardiovascular and respiratory health.

A large international meta-analysis published in the New England Journal of Medicine Evidence, based on nearly 1.5 million individuals from the United States, Canada, Norway, and the United Kingdom, demonstrated that active smokers have approximately triple the mortality risk of non-smokers and lose an average of 12–13 years of life. However, the benefits of cessation were surprisingly rapid: in people who quit before age 40, about 90–95% of the excess risk was eliminated within the first few years (Cho et al., 2024) [9].

This study suggests a very important physiological concept: a significant portion of the damage caused by smoking depends on reversible processes. When tobacco exposure is interrupted, systemic inflammation, oxidative stress, platelet hyperactivation, and chronic vasoconstriction decrease rapidly. In other words, the body stops receiving continuous toxic signals and can progressively realign many altered biological mechanisms.

The same study showed that those who had quit for over ten years regained about ten years of life expectancy, reaching a survival rate very close to that of non-smokers. This means that the risk does not remain static over time, but evolves progressively based on the duration of abstinence (Chen et al., 2024) [10].

US epidemiological data also strongly confirm this concept. An analysis of over 550,000 American adults showed that smoking significantly increases mortality across all ethnic and racial groups and in both sexes, but that the benefits of cessation are remarkably consistent and universal. Quitting smoking before age 45 reduced excess mortality by about 90%, bringing the risk very close to that of non-smokers (Thomson et al., 2022) [11].

This finding is extremely important from a public health perspective because it suggests that the body possesses a sort of “recoverable biological memory.” The earlier exposure is interrupted, the greater the probability that cellular repair systems will be able to limit the cumulative consequences of oxidative and mutagenic damage.

Smoking cessation takes on even more crucial importance in the oncological context. For a long time, it was thought that quitting smoking after a cancer diagnosis had limited utility, almost irrelevant compared to the severity of the existing disease. Modern evidence has completely overturned this idea.

A large systematic review including over 17,000 oncology patients who smoked demonstrated that quitting smoking after diagnosis is associated with a significant improvement in overall survival, progression-free survival, and disease control. Patients who stopped smoking had about 30% less mortality risk compared to those who continued to smoke (Caini et al., 2026) [12].

From a biological point of view, this result is perfectly plausible. Continuing to smoke during an oncological illness means keeping processes active that promote inflammation, tumor angiogenesis, immunosuppression, and cellular damage. Quitting smoking, on the other hand, reduces tumor proliferation, improves the response to chemotherapy and radiotherapy, decreases postoperative complications, and lowers the risk of developing second primary tumors (Caini et al., 2026) [12].

An oncological diagnosis is defined in many studies as a “teachable moment,” that is, a biologically and psychologically decisive moment in which the patient can concretely modify their prognosis. This profoundly changes the way we interpret cessation: no longer just future prevention, but an integral part of the therapy itself.

A particularly clear example concerns head and neck cancers. A meta-analysis that included 65 studies demonstrated that ex-smokers have about half the risk of developing these cancers compared to active smokers. The protective effect began within the first five years of abstinence and continued to increase progressively over time; the dose-response data are particularly impressive: every ten years of cessation was associated with a risk reduction of about 50%. After more than twenty years, the risk tended to approach that of non-smokers (Khalifeh et al., 2024) [13].

This trend suggests that smoking influences not only the onset of carcinogenesis but also the later stages of tumor progression. Interrupting tobacco exposure therefore means progressively reducing the biological stimulus that fuels cellular transformation. Overall, all scientific evidence converges toward an extremely consistent message: quitting smoking produces profound, progressive, and biologically concrete benefits at any age and at any stage of disease. Recovery is not immediate or absolute, but the body quickly begins to reduce the inflammatory, oxidative, and thrombotic burden accumulated over the years.

Cessation does not completely erase the biological past of smoking, but it significantly modifies the physiological future of the organism. Every year without tobacco represents time gained for the cardiovascular, respiratory, immune, and cellular systems. And it is precisely this progressive reconquest of biological homeostasis that makes smoking cessation one of the most powerful and measurable interventions in all of preventive medicine.

In recent years, vaping has won over millions of people, quickly becoming a daily habit for both adolescents and adults with the promise of being a “safer” alternative to traditional smoking. However, this widespread adoption makes it essential to analyze the phenomenon carefully, looking beyond marketing and common perceptions.

As scientific evidence has progressively accumulated, a much more complex picture has emerged: while electronic cigarettes may reduce exposure to some toxic substances typical of combustion, this does not mean they are biologically harmless.

The aerosols produced by these devices are not simply “water vapor,” as they are often perceived. Instead, they are mixtures containing nicotine, propylene glycol, glycerol, chemical flavorings, aldehydes, ultrafine particles, and heavy metals—substances capable of interacting directly with respiratory tissue, the cardiovascular system, and numerous cellular processes (Petrella et al., 2025) [14].

From a pathophysiological perspective, many of the mechanisms observed in vaping resemble those already known in traditional smoking: oxidative stress, inflammation, endothelial dysfunction, DNA damage, and mitochondrial alterations. In practice, even though the mode of exposure changes, the body continues to receive potentially harmful biological stimuli.

One of the most concerning aspects is the spread of vaping among adolescents. Electronic cigarettes are often perceived by young people as “clean,” modern, and less dangerous products compared to conventional cigarettes. Sweet flavors, aggressive marketing, and social pressure have favored a very rapid increase in their use among the youngest segments of the population (Petrella et al., 2025) [14].

However, respiratory evidence is becoming increasingly consistent. A meta-analysis including nearly half a million adolescents demonstrated that electronic cigarette use is associated with a significant increase in the risk of asthma. The association was present in both current and former users and persisted even in subjects who used electronic cigarettes exclusively, regardless of traditional smoking (Li et al., 2022) [15].

This finding is particularly important because it suggests that vaping itself may contribute directly to bronchial inflammation. Inhaled aerosols appear to increase airway hyperreactivity and promote bronchoconstriction and bronchial eosinophilia (an increase in the number of eosinophils in the blood, a type of white blood cell involved primarily in allergic reactions). It is as if the airways were being exposed daily to a cloud of micro-irritants capable of maintaining a persistent state of inflammation.

Respiratory alterations associated with electronic cigarettes are not limited to asthma. The most recent evidence also shows a significant association with chronic bronchitis, emphysema, and chronic obstructive pulmonary disease (COPD) (Petrella et al., 2025) [14].

A recent meta-analysis of 15 observational studies showed that current electronic cigarette users have a significant increase in the risk of COPD even after adjusting for traditional smoking. The association was present not only in current users but also in former users and subjects with prolonged habitual use; from a biological standpoint, these results are consistent with mechanisms observed experimentally. Electronic cigarette aerosols can induce chronic airway inflammation, increase metalloproteinases (enzymes that degrade proteins and contribute to tissue remodeling) involved in lung remodeling, and cause direct epithelial damage. Furthermore, aldehydes and heavy metals present in inhaled liquids can amplify oxidative stress and accelerate the degeneration of lung tissue (Malvi et al., 2025) [16].

In recent years, a new acute respiratory syndrome associated with vaping has also emerged: EVALI, or E-cigarette or Vaping Associated Lung Injury. This condition can manifest with bilateral pulmonary infiltrates, respiratory failure, and diffuse alveolar damage. In many cases, products containing THC and vitamin E acetate have been identified, but the phenomenon has highlighted how the toxic effects of vaping can be sudden and potentially severe (Petrella et al., 2025) [14].

The picture is also becoming progressively clearer regarding the cardiovascular system. Although electronic cigarettes were initially considered a cardiovascularly safer alternative, epidemiological and experimental evidence indicates that inhaled aerosols can profoundly alter vascular function.

A recent systematic review and meta-analysis showed that electronic cigarette use is associated with a significant increase in the risk of myocardial infarction. The association persisted even after correction for traditional smoking, suggesting an independent effect of vaping. The risk was particularly high in former smokers who had replaced conventional cigarettes with electronic ones (Gupta et al., 2026) [17].

These results find a plausible biological explanation. The nicotine contained in the aerosols acts as a potent sympathetic stimulant, increasing heart rate, blood pressure, and myocardial oxygen demand (Al-Rubaye et al., 2026) [18]. Simultaneously, ultrafine particles and volatile organic compounds promote oxidative stress, endothelial dysfunction, and platelet aggregation (Gupta et al., 2026) [17].

In practice, the cardiovascular system continues to receive pro-atherosclerotic and pro-thrombotic biological signals, very similar to those observed in conventional smoking. It is as if the blood vessels were being kept in a chronic state of irritation and instability.

A more recent meta-analysis directly compared electronic cigarettes, traditional cigarettes, combined use, and non-use. The results showed that vaping is associated with an increase in overall cardiovascular risk, although lower than that of traditional smoking. However, the most concerning data involved so-called “dual users,” i.e., people who smoke both traditional and electronic cigarettes: in this group, the cardiovascular risk was even higher (Tansawet et al., 2025) [19].

This aspect is fundamental because, in clinical practice, many subjects do not completely replace traditional smoking with vaping but use them simultaneously. In these cases, instead of actually reducing harm, there is a risk of adding different toxic exposures together.

A further meta-analysis including over 900,000 participants confirmed an association between electronic cigarette use and an increased risk of major cardiovascular events, stroke, and coronary heart disease. In this case, too, the highest risk was observed in dual users (Al-Rubaye et al., 2026) [18].

Current evidence therefore suggests that electronic cigarettes cannot be considered risk-free devices. It is true that the absence of combustion reduces exposure to some highly toxic substances present in traditional cigarettes, but this does not equate to biological safety. Vaping introduces new modes of chemical exposure that are still relatively recent, the long-term effects of which are likely underestimated due to the limited observation time available.

A particularly delicate aspect concerns pregnancy. Recent studies indicate that vaping during gestation is associated with an increase in adverse maternal and neonatal outcomes, including preterm birth and low birth weight. Experimental models also show alterations in fetal lung and neurological development, suggesting that inhaled substances can cross the placenta and interfere with the fetus's biological programming (Petrella et al., 2025) [14].

Overall, the picture emerging from modern scientific literature is very different from the initial image of electronic cigarettes as essentially harmless devices. Current evidence indicates that ENDS (electronic devices, such as e-cigarettes) can contribute to chronic inflammation, respiratory alterations, vascular damage, and increased cardiovascular risk, especially in young people and dual users.

This does not necessarily mean that electronic cigarettes have the same level of toxicity as conventional smoking, but it does mean that the concept of a “safe alternative” does not currently find real scientific support. The body continues to be exposed to biologically active substances capable of altering cellular, respiratory, and cardiovascular functioning. And it is precisely this continuity of biological damage, even in the absence of traditional combustion, that represents one of the most important and often underestimated aspects of vaping.

The link between cigarette smoking and insulin resistance is today one of the most significant and, for many years, one of the most underestimated aspects of cardiovascular and metabolic pathophysiology. For a long time, smoking was considered primarily a respiratory or vascular problem. However, with the progressive accumulation of scientific evidence, it has emerged that smoking also acts profoundly on glucose metabolism, altering tissue sensitivity to insulin and promoting a metabolic profile extremely similar to metabolic syndrome.

Under physiological conditions, insulin acts as a sort of “biological key” that allows glucose to enter cells. When insulin resistance occurs, this key continues to be produced, often in high quantities, but cells progressively begin to “not respond” correctly to the insulin signal. Consequently, the pancreas is forced to compensate by producing ever-increasing amounts of insulin, generating the condition known as compensatory hyperinsulinemia.

The first direct evidence of this phenomenon in smokers emerged as early as the early 1990s. A pioneering study demonstrated that chronic smokers exhibited reduced insulin-mediated glucose uptake, accompanied by hyperinsulinemia and a typical atherogenic lipid profile characterized by elevated triglycerides and reduced HDL cholesterol (Facchini et al., 1992) [20].

A particularly interesting element that emerged from this study was that glycemic levels appeared relatively normal, while the insulin response was clearly increased. This means that the pancreas was initially able to compensate for the metabolic defect by increasing insulin secretion. In practice, the metabolic engine was still able to maintain balance, but only by constantly working “over-revved.”

In subsequent years, further studies confirmed this relationship. A large epidemiological analysis of non-diabetic men showed that smokers had significantly higher plasma insulin levels compared to non-smokers, regardless of age, BMI (the most commonly used parameter to assess body weight), blood pressure, physical activity, and alcohol consumption. Former smokers showed intermediate values, suggesting a possible, at least partial, reversibility of insulin resistance after smoking cessation (Rönnemaa et al., 1996) [21].

This aspect is very important from a pathophysiological point of view. It means that smoking does not just directly damage blood vessels or the respiratory system, but also profoundly alters the way the body uses energy and nutrients. And it is precisely this chronic metabolic alteration that could explain a significant part of the increased cardiovascular risk observed in smokers.

In the 2000s, the concept of insulin resistance as a “biological bridge” between smoking and cardiovascular disease began to consolidate further. A review published in the Journal of the American College of Cardiology proposed that insulin resistance represented the true central pathophysiological node through which smoking accelerates atherosclerosis and vascular damage (Reaven and Tsao, 2003) [22].

According to this model, smoking acts as an amplifier of pre-existing metabolic vulnerability. Through an increase in catecholamines (substances produced mainly by the adrenal glands and the nervous system), increased cortisol, oxidative stress, chronic inflammation, and impaired mitochondrial function, smoking progressively compromises peripheral insulin signaling; in other words, smoking progressively transforms the metabolism into an environment favorable to the development of type 2 diabetes and cardiovascular disease.

A particularly relevant aspect that emerged from the literature is the presence of a dose-response relationship. The longer and more intense the exposure to tobacco, the greater the metabolic deterioration. A Tunisian study on non-diabetic subjects demonstrated that the number of cigarettes smoked daily and the duration of exposure were directly correlated with an increase in HOMA-IR (a blood test that estimates insulin resistance and pancreatic cell function) and plasma insulin levels (Haj Mouhamed et al., 2016) [23].

Furthermore, smokers had significantly higher concentrations of fasting glycemia, insulin, and insulin resistance compared to non-smokers, even after adjustment for age, BMI, sex, and alcohol consumption.

In recent years, studies have begun to use objective biomarkers of tobacco exposure, overcoming the limitations of self-reported questionnaires. A Korean study based on urinary levels of cotinine and NNAL (two main biomarkers) confirmed that habitual smokers have a significantly higher risk of high insulin resistance compared to non-smokers; the interesting finding is that even former smokers still showed an increased risk, suggesting that the metabolic effects of tobacco can persist for a certain period even after cessation. Furthermore, the risk was particularly high in sedentary subjects with high BMI and habitual alcohol consumption (Cho et al., 2022) [24].

This suggests an extremely important synergy between lifestyle factors. Smoking does not act in isolation, but amplifies other pre-existing metabolic vulnerabilities. Sedentary lifestyle, visceral obesity, and dysfunctional diet create a biological terrain upon which smoking exerts an even more aggressive effect.

Electronic cigarettes also seem to share some of these metabolic effects. A recent study highlighted that electronic cigarette users have TyG index values (a marker used in clinical practice to estimate insulin resistance) significantly higher than non-smokers. After correcting for the main confounding variables, vaping was associated with a significant increase in the risk of insulin resistance (Lim et al., 2025) [25].

These results are consistent with previous observations on dual smokers, i.e., subjects who use both traditional and electronic cigarettes simultaneously. In this group, the metabolic risk appears even higher (Jeong et al., 2021) [26].

The Korean study conducted on smoking behavior and the TyG index has in fact shown that dual smokers had the highest risk of insulin resistance in both men and women.

From a pathophysiological point of view, these data reinforce the idea that the metabolic problem does not depend exclusively on tobacco combustion, but also on the direct action of nicotine and other substances present in the inhaled aerosols.

One of the most interesting aspects that emerged from the literature concerns the specific role of nicotine. For a long time, it was debated whether it was nicotine itself or other smoke compounds that generated insulin resistance. Several studies have provided very strong indications in favor of a direct role for nicotine; in fact, research on chronic users of nicotine gum showed that healthy subjects, despite not having smoked for years, still exhibited significant insulin resistance and compensatory hyperinsulinemia. Insulin sensitivity was inversely correlated with plasma cotinine levels, indicating a dose-dependent relationship between chronic nicotine exposure and metabolic alteration (Eliasson et al., 1996) [27].

Even during smoking cessation programs, a particularly interesting phenomenon emerges. One study demonstrated that during nicotine replacement therapy, insulin sensitivity worsened significantly, while it improved after complete nicotine withdrawal, despite continued body weight gain (Assali et al., 1999) [28].

This finding is extremely important because it contradicts a widespread belief that simple post-cessation weight gain is necessarily synonymous with metabolic worsening. In reality, eliminating nicotine seems to improve insulin sensitivity even when body weight increases.

In practice, the metabolism appears more sensitive to the chronic presence of nicotine than to the moderate weight gain observed after smoking cessation.

Overall, all this evidence converges toward a very clear conclusion: cigarette smoking, nicotine, and even electronic cigarettes are powerful promoters of insulin resistance. This phenomenon constitutes one of the main mechanisms through which smoking increases cardiovascular risk, accelerates metabolic syndrome, and promotes the development of type 2 diabetes.

Smoking, therefore, does not only damage the lungs or blood vessels. By progressively altering insulin sensitivity, it modifies the very heart of human energy metabolism. And when the metabolism loses the ability to correctly manage glucose, lipids, and insulin, the entire organism slowly enters a biological state favorable to chronic inflammation, atherosclerosis, and systemic metabolic degeneration.

The relationship between nicotine and the PI3K/AKT/mTOR pathway represents one of the most important turning points in the modern understanding of the metabolic effects of smoking. For many years, tobacco use was interpreted almost exclusively as a source of oxidative stress, inflammation, and vascular damage. Today, however, evidence shows that nicotine is capable of directly interfering with the main intracellular systems that regulate cell growth, energy metabolism, protein synthesis, and insulin sensitivity.

Among these systems, the PI3K/AKT/mTOR pathway occupies a central position. mTOR can be imagined as a sort of "metabolic control center" of the cell: it receives information regarding nutrients, available energy, hormonal signals, and cellular stress status, deciding whether the cell should grow, synthesize proteins, store energy, or slow down its functions to protect itself.

Under physiological conditions, the activation of mTOR is essential for cell survival. However, when this pathway is stimulated chronically or dysfunctionally, it can turn into one of the main drivers of insulin resistance, metabolic inflammation, and cellular aging.

One of the first studies to directly clarify the link between nicotine and mTOR was that of the researcher Bergman, who identified a new molecular mechanism through which smoking induces insulin resistance in skeletal muscle.

The study showed that chronic smokers had a significant reduction in insulin sensitivity compared to non-smokers. The most important discovery, however, concerned what happened inside the muscle cell; nicotine actually increased the activity of the mTOR pathway, leading to greater phosphorylation of IRS-1 (Bergman et al., 2012) [29].

This step is biologically crucial because IRS-1, as we saw in chapter 4 dedicated to the insulin pathway, represents one of the main intermediaries of insulin signaling.

The study demonstrated that exposure to nicotine induced an increase in IRS-1 phosphorylation, a reduction in the insulin response, and a decrease in insulin-mediated glucose uptake.

Even more interesting was the observation that pharmacological inhibition of mTOR using rapamycin prevented these effects and restored insulin sensitivity. This result suggested that mTOR represented the true central node of nicotine-induced insulin resistance (Bergman et al., 2012) [29].

An extremely important aspect that emerged from the study also concerns the reversibility of the phenomenon. After just 1-2 weeks of smoking cessation, subjects showed a significant improvement in insulin sensitivity, a reduction in IRS-1 phosphorylation, and a partial recovery of normal insulin signaling.

Subsequently, a review by the researcher Bajaj further delved into this pathophysiological model, confirming the central role of the mTOR axis in smoking-induced insulin resistance; according to this interpretation, nicotine activates the sympathetic nervous system, increasing lipolysis and the release of free fatty acids. The excess of circulating lipids progressively alters skeletal muscle metabolism and promotes the chronic activation of mTOR (Bajaj, 2012) [30].

The link between nicotine and the PI3K/AKT/mTOR pathway does not seem to be limited to glucose metabolism, however. Some studies suggest that this system also represents one of the main mechanisms through which nicotine exerts neurobiological effects.

In an experimental model of Parkinson's disease induced by a potent neurotoxin, nicotine showed the ability to reactivate the PI3K-AKT-mTOR pathway previously suppressed by the neurotoxin itself (Zhgenti et al., 2025) [31]. The reactivation of this pathway led to an improvement in mitochondrial function, an increase in ATP production (a fundamental biological process through which cells convert nutrients from food into usable energy), and a recovery of respiratory chain activity.

In this context, mTOR assumed a protective role for neuronal survival. This apparent contradiction highlights a fundamental aspect of cell biology: mTOR is not "good" or "bad" in an absolute sense. Its function depends on the cell type involved, the intensity of the activation, the duration of the stimulus, and the general metabolic context. A similar mechanism has also been observed in the central nervous system under conditions of chronic stress. In murine models (mice subjected to unpredictable stress), nicotine showed neuroprotective effects through the activation of autophagy and PI3K/AKT/mTOR signaling (Xiao et al., 2018) [32].

Nicotine improved neuronal vitality and reduced apoptosis and neuropathological alterations of the hippocampus (a fundamental structure of the human brain located in the temporal lobe); when autophagy was pharmacologically blocked, the protective effects of nicotine disappeared. These results suggest that nicotine possesses a complex ability to modulate mTOR and the pathways linked to autophagy, cell survival, and bioenergetics.

However, from a systemic metabolic point of view, the chronic activation of mTOR induced by nicotine remains strictly associated with insulin resistance, an alteration of insulin signaling, metabolic dysfunction, and an increased cardiovascular and diabetic risk.

Overall, current evidence indicates that nicotine does not act simply as a stimulant, but as a powerful intracellular modulator capable of directly interfering with one of the most important energy regulation systems of the human body.

The PI3K/AKT/mTOR pathway therefore represents one of the main meeting points between energy metabolism, insulin, nutrients, cellular stress, inflammation, and biological aging; and it is precisely through the activation of this cascade that nicotine seems to exert a significant part of its systemic effects on the body.

The link between nicotine, nicotinic acetylcholine receptors (nAChR), and mTOR is now one of the most important mechanisms for understanding how smoking can directly alter cellular biology, influencing proliferation, tumor survival, energy metabolism, and neoplastic progression. For many years, nicotine was considered almost exclusively the molecule responsible for tobacco addiction. However, more recent scientific evidence has profoundly changed this view, showing how it can act as a potent intracellular modulator capable of activating specific membrane receptors and, through them, interfering with some of the main systems that regulate cell growth, protein synthesis, and survival.

Nicotinic acetylcholine receptors belong to the family of ionotropic receptors and, under physiological conditions, participate primarily in neurotransmission. For a long time, it was thought that their presence was limited almost exclusively to the nervous system. Today, however, we know that numerous peripheral tissues, including the lung, prostate, vascular endothelium, and tumor cells, express different subtypes of nAChR. This means that once absorbed, nicotine does not act only at the brain level, but can directly influence the biological behavior of many cells in the body.

One of the first studies to convincingly clarify this mechanism was that of the researcher West, who demonstrated that nicotine and NNK, a potent carcinogen derived from tobacco, are able to rapidly activate the PI3K/AKT pathway in normal human bronchial epithelial cells. The most striking aspect was the speed of the phenomenon: the activation of AKT appeared within minutes of exposure and at concentrations compatible with those observable in chronic smokers (West et al., 2003) [33].

Nicotine acted predominantly through receptors, while NNK showed a greater dependence on the α7-nAChR receptor. Although the signal entry point was different, both substances converged on the same intracellular cascade: PI3K/AKT/mTOR. Once activated, this pathway triggered the phosphorylation of proteins involved in protein synthesis and cell growth (West et al., 2003) [33].

From a biological point of view, this means that nicotine does not just generically "stimulate" the cell, but intervenes directly in the systems that control cell fate. It is as if the cell were constantly receiving an artificial signal for growth and survival, regardless of the actual physiological needs of the tissue.

The study also showed that nicotine and NNK significantly reduced apoptosis induced by oxidative stress, etoposide (an anti-tumor chemotherapy drug), and UV radiation. This aspect is crucial in carcinogenesis. Under normal conditions, a cell that accumulates genetic damage should be eliminated through programmed cell death; however, if pathways like PI3K/AKT/mTOR remain constantly activated, the cell continues to survive despite the damage, increasing the probability of accumulating mutations and progressing toward neoplastic transformation.

In subsequent years, the role of the α7-nAChR receptor has become increasingly central to the understanding of the oncogenic effects of nicotine. A recent review dedicated to lung carcinoma showed that nicotine, through α7-nAChR, potently activates the PI3K/AKT pathway, promoting cell proliferation, angiogenesis, suppression of apoptosis, tumor invasion, and metastasis (He et al., 2024) [34].

In this context, mTOR emerges as one of the main downstream targets of AKT. Its chronic activation increases protein synthesis, cellular metabolism, and the proliferative capacity of the tumor cell. In parallel, the PI3K/AKT/mTOR pathway interacts with other systems involved in tumor survival, including NF-κB, HIF-1α, and VEGF (a cell signaling protein that stimulates the formation of new blood vessels). This creates an extremely complex and self-reinforcing biological network capable of sustaining tumor growth, angiogenesis, and therapeutic resistance (He et al., 2024) [34].

The direct involvement of α7-nAChR was also confirmed in studies on A549 lung adenocarcinoma cells. Some researchers demonstrated that α7 and α9–α10 receptors are essential for nicotine-induced proliferation. Pharmacological or genetic blocking of these receptors completely abolished the activation of AKT and ERK (the final link in the MAPK cellular inflammatory signaling pathway seen in chapter 5) and interrupted the proliferative response (Mucchietto et al., 2018) [35].

One of the most interesting aspects was that these effects appeared even at very low concentrations of nicotine, comparable to those normally present in the blood of smokers. This suggests that massive toxic exposures are not necessary to alter cellular signaling: chronic and continuous exposure seems sufficient to keep proliferative pathways constantly active.

An additional level of complexity emerged in a 2009 study, which identified a new nicotine–α7 nAChR–PI3K/AKT/mTOR molecular axis. Nicotine significantly increased the expression of a nuclear receptor in lung carcinoma cells through a mechanism dependent on both α7-nAChR and the PI3K/mTOR pathway. In parallel, nicotine reduced the activity of AP-2α, an important factor with tumor-suppressive function (Sun et al., 2009) [36].

In practice, nicotine not only activated proliferative pathways but simultaneously reduced the intracellular systems that normally limit neoplastic growth. This dual effect creates a cellular environment strongly favorable to tumor progression.

The role of nAChRs does not seem to be limited to lung carcinoma. In prostate carcinoma, significant overexpression of the α5-nAChR subunit has been observed in tumor tissues. Silencing α5-nAChR reduced cell proliferation, migration, and invasion, while simultaneously increasing apoptosis (the programmed elimination of a cell). In this case, too, the phenomenon was associated with a reduction in the phosphorylation of AKT and ERK, suggesting that different receptor subtypes can converge on the same intracellular cell survival systems (Qi et al., 2020) [37].

The centrality of the α7-nAChR → AKT/mTOR axis has been further confirmed by pharmacological studies with selective antagonists. Some researchers demonstrated that the α7-nAChR antagonist QND7 was able to induce apoptosis, reduce proliferation, and inhibit cell migration by suppressing AKT/mTOR signaling. The anti-tumor effect was comparable to that of cisplatin (a potent platinum-based anti-neoplastic chemotherapy drug) in some lung carcinoma cell lines (Witayateeraporn et al., 2020) [38].

This data is extremely important because it suggests that nicotinic receptors do not represent simple passive markers of the disease, but true functional regulators of tumor survival. In other words, nicotine seems to exploit receptors physiologically destined for neurotransmission to keep intracellular pathways active that favor growth, resistance to apoptosis, and neoplastic progression.

Other researchers also showed that nicotine and NNK rapidly activate AKT in both small-cell and non-small-cell lung carcinoma. The activation of AKT induced phosphorylation of mTOR and an increase in proteins that regulate cell cycle progression, promoting clonal expansion (multiplication of a cell into many similar copies) and tumor proliferation. Furthermore, nicotine showed marked anti-apoptotic activity mediated by NF-κB (a group of transcription factors that promote growth, cell survival, and inflammation), offering a possible biological explanation for the worsening prognosis observed in patients who continue to smoke during oncological treatments (Tsurutani et al., 2005) [39].

Overall, all this evidence converges toward an extremely coherent pathophysiological model. Nicotine binds to specific nicotinic acetylcholine receptors, especially α7-nAChR, inducing an intracellular cascade centered on the PI3K/AKT/mTOR axis. This molecular network promotes cell proliferation, protein synthesis, metabolic survival, angiogenesis, and resistance to apoptosis, creating a biological environment favorable to tumor progression and therapeutic resistance.

Nicotine, therefore, does not act simply as a stimulant substance or a molecule responsible for addiction. Through the activation of nAChRs, it behaves as a potent intracellular regulator capable of interfering directly with the main systems that control growth, metabolism, and cell fate.

Among the most potent and studied carcinogens derived from tobacco is the compound NNK (Nicotine-derived Nitrosamine Ketone). Unlike nicotine, which is not considered directly mutagenic, NNK possesses an extremely dangerous dual biological capacity: on one hand, it can directly damage DNA through the formation of mutagenic adducts (chemical alterations of DNA that can cause mutations), and on the other, it is capable of activating intracellular pathways that promote cell survival, proliferation, and tumor progression. This combination makes NNK a sort of "complete accelerator" of carcinogenesis: it not only increases the probability that a cell will develop mutations, but also helps damaged cells survive and proliferate.

In recent years, it has become increasingly clear that a large part of the biological effects of NNK depends on the activation of nicotinic acetylcholine receptors, particularly α7-nAChR. This receptor, initially studied primarily in the nervous system, is now considered one of the main mediators of lung tumorigenesis associated with smoking. NNK, in fact, has a high affinity for α7-nAChR, often even higher than that of nicotine itself, and through this binding, it is able to activate a complex network of intracellular signals centered on the PI3K/AKT/mTOR axis.

One of the first studies to directly demonstrate this mechanism was that of West and colleagues, who observed how exposure to NNK rapidly activated the PI3K/AKT pathway in normal human bronchial epithelial cells. The activation appeared within minutes and specifically involved the α7-nAChR receptor. Once AKT was activated, the phosphorylation of numerous intracellular effectors involved in cell growth increased, including mTOR (West et al., 2004) [41].

From a biological standpoint, this means that NNK is capable of rapidly transforming the metabolic behavior of the cell: it is as if a system designed to activate temporarily in response to physiological stimuli were instead kept constantly switched on. The consequence is a cell that continues to grow, synthesize proteins, and survive even when it should physiologically stop or undergo apoptosis.

The same study also showed that NNK increased cellular resistance to different forms of stress, including UV radiation, oxidative stress, and chemotherapeutic agents. This aspect is extremely important because it suggests that the tobacco carcinogen does not only favor the onset of the tumor, but may also contribute to its aggressiveness and therapeutic resistance (West et al., 2004) [41].

In subsequent years, the role of the NNK–nAChR–AKT/mTOR axis in lung carcinogenesis has been further investigated. A review by some researchers identified the AKT/mTOR pathway as one of the main molecular nodes of tobacco-induced lung tumorigenesis. The authors emphasized that smoking does not promote cancer only through genetic mutations, but also through continuous biochemical modulation of the intracellular systems that regulate cell survival and proliferation (Memmott and Dennis, 2010) [40].

According to this model, NNK acts on two simultaneous levels. On one hand, it produces DNA adducts capable of generating mutations in crucial genes; on the other, it activates nicotinic receptors that stimulate proliferative pathways such as PI3K/AKT/mTOR. In practice, the carcinogen simultaneously creates the genetic damage and the biological conditions that allow mutated cells to survive and expand.

This view of carcinogenesis is profoundly different from the traditional one. The tumor is no longer interpreted as a simple random accumulation of mutations, but as the result of a cellular environment continuously pushed toward growth, metabolic adaptation, and apoptotic resistance.

One of the most interesting aspects that emerged from experimental studies concerns the fact that the activation of the PI3K/AKT/mTOR pathway appears very early during neoplastic transformation. West and colleagues demonstrated, in fact, that human bronchial cells transformed through chronic exposure to NNK showed a marked, persistent activation of AKT and its substrates (West et al., 2004) [41].

These cells showed a significantly superior ability to survive under conditions of growth factor deprivation and stress. The activation of AKT also influenced fundamental regulators of apoptosis, reducing the expression of pro-apoptotic genes.

In other words, the cell not only proliferated more, but progressively lost the ability to "commit suicide" when damaged. This represents one of the key steps in tumor transformation.

The in vivo observation was also particularly important. In mice treated with NNK, the activation of AKT and mTOR increased progressively in parallel with the evolution of lung lesions, from the first areas of hyperplasia to lung adenomas (West et al., 2004) [41]. This suggests that the dysregulation of the PI3K/AKT/mTOR pathway is not a late event, but one of the first biological changes in tobacco-induced carcinogenesis.

A further mechanism of cell survival emerged in the study by Jin and colleagues, which analyzed the role of the protein survivin in bronchial cells exposed to nicotine and NNK (Jin et al., 2008) [42]. Survivin belongs to the family of apoptosis inhibitor proteins and is normally almost absent in healthy adult tissues, while it is strongly expressed in tumors; the study showed that both nicotine and NNK significantly increased the expression of survivin in human bronchial cells through the activation of the AKT/mTOR pathway. The increase in survivin improved cell survival and favored the malignant transformation of cells exposed to tobacco components.

From a pathophysiological point of view, the significance is very profound. The cell exposed to NNK does not just proliferate more rapidly: it becomes progressively less sensitive to the signals that normally eliminate damaged cells. It is as if the body's quality control system were being progressively deactivated.

Retrospective clinical studies have also shown extremely relevant implications of these mechanisms. Some researchers highlighted that patients with tobacco-related tumors who continued to smoke after diagnosis had worse survival and a lower therapeutic response.

At the cellular level, nicotine and NNK rapidly activated AKT and increased the phosphorylation of mTOR and tuberin. This promoted cell proliferation and tumor survival. Nicotine, moreover, showed strong anti-apoptotic activity mediated by NF-κB (Tsurutani et al., 2005) [39].

These data help to understand why smoking continues to worsen oncological prognosis even after the tumor has already developed. Tobacco components, in fact, continue to fuel intracellular pathways that support tumor growth, apoptotic resistance, and metabolic adaptation.

In recent years, the possibility of pharmacologically interfering with this molecular axis has also emerged. A study on β-cryptoxanthin, a carotenoid present in citrus fruits and red peppers, showed that this molecule was able to significantly reduce NNK-induced lung tumorigenesis in mice.

The effect was associated with a marked downregulation of α7-nAChR and the inhibition of the PI3K/AKT pathway. Furthermore, β-cryptoxanthin reduced migration, cell invasion, and the formation of lamellipodia (leaf-shaped cytoplasmic extensions that form on the surface of cells during cell migration) in α7-nAChR-positive tumor cells (Iskandar et al., 2016) [43].

This study is particularly interesting because it suggests that the α7-nAChR/PI3K/AKT/mTOR axis may represent not only a central pathological mechanism of tobacco-related carcinogenesis, but also a potential therapeutic and chemopreventive target.

Overall, all the evidence converges toward an extremely coherent biological model. NNK does not act only as a direct mutagenic agent, but exploits nicotinic acetylcholine receptors, especially α7-nAChR, to stably activate the insulin pathway cascade. This cascade increases cell proliferation, protein synthesis, metabolic adaptation, and apoptotic resistance, creating an ideal biological environment for neoplastic transformation and tumor progression.

The final result is a cell that not only accumulates genetic damage, but also progressively acquires the ability to survive, proliferate, and adapt to conditions that would normally cause its death. And it is precisely this combination of genetic damage and aberrant survival that makes NNK one of the most potent carcinogens contained in tobacco.

One of the main biological models through which smoking is interpreted not only as an initial carcinogenic factor, but also as a powerful promoter of the growth and survival of neoplastic cells, is the link between nicotine, nicotinic acetylcholine receptors, and tumor progression. For many years, oncological research focused almost exclusively on the ability of tobacco to induce genetic mutations. Today, it is becoming increasingly evident that nicotine can also act in a profoundly different way: not necessarily by creating new mutations, but by directly altering the intracellular systems that regulate cell growth, apoptosis, angiogenesis, metabolic adaptation, and therapeutic resistance.

One of the most important aspects that has emerged in recent years concerns the role of nicotinic acetylcholine receptors, especially α7-nAChR, α9-nAChR, and α5-nAChR. These receptors, originally studied in the nervous system, have also been identified in numerous tumor tissues, including the lung, stomach, oral cavity, and bladder. When nicotine binds to these receptors, the cell activates a complex intracellular cascade dominated by the PI3K/AKT/mTOR pathway, one of the main systems that control cell growth, protein synthesis, and cell survival.

It is as if nicotine transforms nAChR receptors into a sort of "biological accelerator" that is constantly pressed, keeping the proliferative signals of the tumor cell continuously active.

One of the first studies to clarify this phenomenon was that of West and colleagues, which demonstrated how nicotine and NNK rapidly activate the PI3K/AKT pathway in normal human bronchial epithelial cells. The activation appeared within minutes of exposure and involved different receptor subtypes: α3/α4 for nicotine and α7-nAChR for NNK (West et al., 2004) [41].

The phosphorylation of AKT subsequently determined the activation of various downstream effectors involved in cell growth and protein synthesis. These pathways increased cell proliferation and resistance to apoptosis, simultaneously favoring characteristics compatible with early neoplastic transformation.

Cells exposed to nicotine, in fact, showed loss of contact inhibition, reduced dependence on growth factors, and less need for adhesion to the extracellular matrix. In simple terms, the cell progressively began to behave like a tumor cell even before the appearance of a clinically evident tumor.

The study also showed that nicotine and NNK significantly reduced cell death induced by etoposide, UV radiation, and hydrogen peroxide. This step is biologically crucial: a cell that accumulates genetic damage should normally undergo apoptosis. However, if pathways like AKT and mTOR remain constantly activated, the damaged cell continues to survive, progressively increasing the risk of neoplastic transformation (West et al., 2004) [41].

In subsequent years, the role of the α7-nAChR/PI3K/AKT/mTOR axis in lung carcinoma has been further investigated. A recent review showed that nicotine, through α7-nAChR, promotes tumor proliferation, angiogenesis, metastasis, epithelial-mesenchymal transition (a process important in embryonic development and tissue repair), and resistance to apoptosis (He et al., 2024) [34].

According to this pathophysiological model, the persistent activation of PI3K/AKT subsequently determines the stimulation of mTOR, NF-κB, HIF-1α, and VEGF: the result is an extremely complex biological network that simultaneously supports cell growth, protein synthesis, metabolic adaptation, the formation of new blood vessels, and tumor invasiveness.

The activation of HIF-1α and VEGF is particularly important because it promotes tumor angiogenesis. In practice, the tumor progressively acquires the ability to build new blood vessels to fuel its own growth and facilitate metastatic spread.

In parallel, nicotine promotes the epithelial-mesenchymal transition, a process during which tumor cells lose the typical characteristics of epithelial cells and acquire greater mobility and invasiveness (He et al., 2024) [34]. It is a fundamental step in the development of metastases.

A particularly interesting element that emerged from experimental studies concerns the fact that not all tumor cells respond to nicotine in the same way. Some researchers demonstrated that the proliferative response depends heavily on the receptor profile expressed by the tumor (Mucchietto et al., 2018) [35].

In specific lung adenocarcinoma cells, characterized by high expression of α7 and α9-nAChR, nicotine induced marked cell proliferation and rapid activation of AKT and ERK. Conversely, different cells with low expression of α7-nAChR were much less sensitive to the proliferative effects of nicotine.

This suggests that some tumors may become particularly dependent on nicotinic signaling. In practice, the tumor develops a sort of "biological addiction" to nicotine to support its own growth.

The study also showed that the pharmacological or genetic blocking of α7 and α9 receptors completely abolished the activation of AKT and ERK and interrupted cell proliferation. The use of a potent synthetic antagonist also proved capable of effectively blocking these pathways, reducing proliferation and increasing the production of intracellular ROS (reactive oxygen species) (Mucchietto et al., 2018) [35].

These results suggest that nicotinic receptors do not simply represent passive tumor markers, but true functional regulators of neoplastic growth.

Another extremely important aspect concerns chemoresistance. Numerous studies show, in fact, that nicotine not only promotes tumor growth but also reduces the effectiveness of oncological treatments.

Researchers demonstrated that nicotine and NNK rapidly activate AKT and mTOR in lung tumor cells, promoting cell proliferation and NF-κB-mediated survival. Nicotine also showed strong anti-apoptotic activity, significantly reducing cell death induced by metabolic stress and chemotherapy (Tsurutani et al., 2005) [39].

From a clinical point of view, this phenomenon could explain why patients who continue to smoke after an oncological diagnosis often present a worse therapeutic response, greater tumor progression, and reduced overall survival.

A very similar picture has also been observed in gastric carcinoma. Researchers in a study on the subject demonstrated that nicotine activates the α5-nAChR/AKT pathway in human gastric tumor cells, increasing cell proliferation and reducing apoptosis induced by cisplatin (Jia et al., 2016) [44].

Nicotine increased the expression of anti-apoptotic proteins and survivin (a protein that promotes cell survival and division), while simultaneously reducing Bax and Caspase-3 (two key players in the apoptosis process). When the PI3K/AKT pathway was pharmacologically blocked, apoptosis was restored: this means that nicotine can literally "protect" tumor cells from the effects of chemotherapy.

Very similar results have also been observed in oral carcinoma. In one study, it was demonstrated that nicotine significantly increases the survival of squamous cells, reducing apoptosis induced by cisplatin through the activation of α7-nAChR (Hsu et al., 2020) [45].

Cells treated with nicotine maintained high levels of Bcl-2 (a fundamental protein that regulates cell survival) even during exposure to cisplatin. The pharmacological or genetic blocking of α7-nAChR significantly attenuated these effects, suggesting that the receptor represents a central node of nicotine-induced chemoresistance.

Analogous results have also been observed in bladder carcinoma. Some researchers demonstrated that nicotine increases cell proliferation and tumor growth through activation of the PI3K/AKT/mTOR pathway; exposure to nicotine increased the expression of AKT, while reducing the efficacy of cisplatin both in vitro and in animal models. Particularly interesting was the effect of the dual PI3K/mTOR inhibitor NVP-BEZ235, which was capable of blocking nicotine-induced proliferation and restoring sensitivity to chemotherapy (Yuge et al., 2015) [46].

Overall, all these findings converge toward an extremely coherent biological model. Nicotine activates specific nicotinic acetylcholine receptors present on tumor cells, especially α7-nAChR, α9-nAChR, and α5-nAChR. This activation stimulates the PI3K/AKT/mTOR cascade, favoring tumor growth, protein synthesis, angiogenesis, metabolic adaptation, apoptotic resistance, and chemoresistance.

The tumor, therefore, is not fueled only by the initial mutations induced by tobacco, but also by a continuous biological stimulation that sustains its growth and survival over time. Nicotine acts as a true oncogenic modulator capable of transforming receptors physiologically intended for neurotransmission into powerful activators of proliferative pathways.