Smoker's Lungs: Quo Vadis? Exploring the Shared and Individual Smoking‐Related Molecular Pathways of Emphysema, Carcinoma, and Fibrosis – An Illustrative Review

ABSTRACT

Cigarette smoking is a major preventable risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD); furthermore, it is also associated with idiopathic pulmonary fibrosis (IPF). Cigarette smoke primarily induces chronic epithelial injury in the lungs, initiating a cascade of interconnected molecular responses within the pulmonary microenvironment. Aiming to explore the common and individual important pathways in the processes of malignant alteration (non‐small cell carcinoma), lung tissue destruction (emphysema in the context of COPD), and aberrant healing (IPF), we conducted a narrative review in which we explore the roles of various selected processes, including NFκB activation, mitochondrial dysfunction, the role of reactive oxygen species, and the antioxidant response via Keap1/Nrf2 and TGFβ‐mediated signaling, in the context of their respective disease. This review is not meant to represent an exhaustive reference of pathophysiologic processes involved in the pathogenesis of these diseases, but to illustrate the common features and specific differences among the selected disease processes. Given the persistent global burden of tobacco use, further research into the interconnected molecular consequences of cigarette smoke exposure remains essential for advancing both preventive and therapeutic approaches in pulmonary medicine.

Cigarette smoking is related to chronic epithelial injury, which represents a central initiating event in smoking‐related lung diseases: NSCLC (non‐small cell lung cancer), IPF (idiopathic pulmonary fibrosis), and emphysema. Altered lung biology and shared molecular pathways contribute to their pathogenesis.

1. Introduction

Cigarettes contain more than 7000 chemicals, many of which have well‐recognized noxious effects on humans [1]. Smoking is detrimental to the health of almost every organ system, most notably the respiratory system [2, 3]. The vast scale of the problem is best visualized by the fact that over a fifth of the world population (ab)uses tobacco: the estimated global prevalence of tobacco use in 2020 was 21.7%, being more prevalent in men (35.5%) than in women (7.9%) [4].

In the Western world, cigarette smoke is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD), but is also associated with idiopathic pulmonary fibrosis (IPF) [1, 5, 6, 7, 8]. Due to its extremely addictive nature, smoking cessation is a major challenge. Nicotine addiction works by activating the brain's reward system pathways, which in turn stimulate the release of dopamine in the brain, creating pleasurable sensations which reinforce the desire to repeatedly (ab)use nicotine [1, 9].

This neurobiological reinforcement also ensures the repeated exposure of tissues to damaging cigarette smoke [1, 5, 9]. To generalize, cigarette smoke primarily induces chronic epithelial injury in the lungs, initiating a cascade of interconnected molecular responses within the pulmonary microenvironment [10, 11, 12, 13]. Depending on the dominant downstream pathways activated in the injured epithelium and surrounding tissue, distinct diseases may develop. Rather than acting in isolation, several processes unfold simultaneously and influence one another as the disease advances in an individual patient.

Combined pulmonary fibrosis and emphysema (CPFE), with emphysema predominantly located in the upper and fibrosis in the lower lobes, often coexist [14, 15, 16]. Additionally, both COPD and pulmonary fibrosis are established risk factors for lung cancer development [17, 18, 19, 20, 21, 22, 23]. Patients with CPFE may face an even higher risk than those with a single underlying pattern, such as fibrosis or emphysema alone [24, 25].

In this narrative review, we wished to explore the shared and individual major molecular pathways implicated in the smoking‐related or associated pathogenesis of three major disease processes: neoplastic (namely, e.g., non‐small cell lung cancer – (NSCLC)), lung tissue destruction (emphysema, a COPD phenotype) and aberrant lung healing (i.e., lung fibrosis [especially IPF]). We chose NSCLC, emphysema and IPF as examples of these three major “disease patterns.” It is worth noting that, as the pathogenesis of each of these diseases is extremely complex, multifactorial and incompletely understood, we aimed our focus to the main pathways/homeostatic axes which seem to be dysregulated by chronic exposure to cigarette smoke.

2. Chronic Smoking Leads to Neoplastic Genesis: Non‐Small Cell Lung Cancer

NSCLC is the most common group of lung cancers, accounting for 85% of patients, while adenocarcinoma is (currently) the most common type of NSCLC. NSCLC primarily derives from epithelial cells, and more specifically, adenocarcinoma usually arises from type II alveolar cells [26]. Despite significant advances in research, the survival rate for NSCLC remains very poor, highlighting the need for ongoing research and knowledge on the impact of modifiable risk factors, such as cigarette smoking [27, 28, 29]. Chronic cigarette smoking drives carcinogenesis through the accumulation of somatic mutations, epigenetic reprogramming, persistent inflammatory signaling, and metabolic alterations [28, 30, 31, 32, 33].

Large‐scale genomic analyses have demonstrated that tobacco exposure increases cancer risk primarily by accelerating the accumulation of somatic mutations via multiple mutational processes, rather than through a single dominant mechanism [31, 34]. Directly exposed tissues experience primary toxic and mutagenic injury, with mutational patterns consistent with misreplication of DNA induced by tobacco carcinogens. Additional mutational signatures reflect indirect activation of endogenous mutagenic processes, similar to those in nearby tissues that are influenced by secondary inflammatory and signaling‐driven effects [31, 34, 35, 36].

At the level of histologically nonmalignant lung tissue, smoking induces a stable and reproducible transcriptomic “field of injury,” characterized by sustained dysregulation of genes involved in xenobiotic metabolism, oxidative stress responses, lipid metabolism, and coagulation pathways [35, 37, 38, 39, 40]. Central to this response is persistent activation of the aryl hydrocarbon receptor (AHR) signaling axis, with upregulation of AHR repressor (AHRR), AhR‐dependent cytochromes 450 (CYP) 1A1 and 1B1, some of which remain incompletely reversible, even decades after smoking cessation, providing a molecular basis for the residual lung cancer risk observed in former smokers [32, 41, 42, 43, 44]. Beyond direct genotoxicity, chronic smoking drives lung carcinogenesis through sustained activation of pro‐inflammatory and pro‐survival signaling networks. Multiple studies identify NF‐κB as a central transcriptional hub activated by smoke‐derived reactive oxygen species, nicotine, and tobacco‐specific nitrosamines, integrating inflammatory cues with cell survival, angiogenesis, epithelial to mesenchymal transition (EMT), and stemness programs crosstalk between NF‐κB and PI3K‐AKT, MAPK, STAT3, and epigenetic regulators amplifies oncogenic signaling and fosters a tumor‐promoting microenvironment [32, 43, 45, 46, 47, 48, 49]. Smoking‐related lung cancer is further shaped by cumulative genetic and epigenetic alterations affecting key oncogenes and tumor suppressor genes, including TP53, kirsten rat sarcoma viral oncogene homolog (KRAS), serine/threonine kinase 11 (STK11), phosphatase and tensin homolog (PTEN), and cyclin‐dependent kinase inhibitor 2A (CDKN2A), as well as recurrent chromosomal losses at 3p, 9p, and 13q [7]. These genetic events are accompanied by aberrant DNA methylation of tumor suppressor genes such as RAS association domain family member 1A (RASSF1A), O6‐methylguanine‐DNA methyltransferase (MGMT), and adenomatous polyposis coli (APC), and by dysregulation of microRNA networks (e.g., let‐7 family, miR‐21, miR‐218), further reinforcing malignant transformation [32]. Impairment of DNA damage recognition and repair represents another critical mechanism by which smoking promotes early lung carcinogenesis. Cigarette smoke‐induced DNA lesions synergize with reduced expression of nucleotide excision repair components, particularly XPC, thus fulfilling a “double‐hit hypothesis” that drives genomic instability in bronchial epithelial cells [50]. This defect allows for accumulation of mutations during early premalignant stages, consistent with the concept of multistep carcinogenesis arising within a smoking‐exposed airway field [51]. Beyond nucleotide excision repair defects, smoking‐induced DNA damage engages broader DNA damage response (DDR) pathways, including ATM/ATR checkpoint signaling, p53‐mediated cell cycle control, and replication stress responses, thereby shaping clonal selection during early lung carcinogenesis [51, 52]. Dysregulated DDR not only facilitates mutation accumulation but also contributes to therapy resistance in established tumors.

Proteomic and phosphoproteomic studies provide additional functional insight into the molecular consequences of chronic smoking in lung cancer, complementing genomic and transcriptomic data. Mass spectrometry‐based analyses of smoking‐related NSCLC consistently reveal dysregulation of redox‐regulated proteins and stress response pathways, including upregulation of peroxiredoxins (PRDX1/2/6), thioredoxin system components (TXN, TXNRD1), superoxide dismutases (SOD1/2), and aldehyde dehydrogenases (ALDH1A1, ALDH3A1), reflecting adaptive responses to cigarette smoke‐induced oxidative stress [35]. Proteomic profiling further highlights alterations in protein folding and proteostasis networks, with increased abundance of HSP90, HSP70, and HSP27, linking chronic smoke exposure to unfolded protein response activation and therapy resistance [53, 54, 55, 56, 57]. Importantly, phosphoproteomic studies demonstrate smoking‐associated activation of kinase‐driven signaling, including increased phosphorylation of AKT, ERK1/2, STAT3, NF‐κB, p65, and MARCKS, which is indicative of inflammatory and survival pathways converging in smoking‐related tumor progression [46, 58]. In addition, proteomic analyses of tumor tissue and secretome identify remodeling of the ECM, with increased expression of MMP2, MMP9, fibronectin (FN1), SPARC, and thrombospondin‐1 (THBS1), which are linked with enhanced invasion, angiogenesis, and metastatic potential [59, 60, 61, 62, 63].

Cigarette smoke exposure also alters intercellular communication through extracellular vesicles (EV). Smoke‐exposed epithelial cells release EVs enriched with inflammatory mediators, microRNAs, and proteins involved in matrix remodeling that modulate macrophage activation, fibroblast differentiation, and tumor microenvironment signaling [64, 65, 66, 67].

Chronic smoking also induces severe metabolic reprogramming that supports tumor growth and progression. A metabolomic study detected altered levels in 343 of the surveyed 930 metabolites, highlighting distinct metabolic disruption [68]. Recent evidence demonstrates that cigarette smoke promotes posttranslational modification of metabolic enzymes, including p300‐mediated succinylation of GAPDH (K251), enhancing glycolytic flux and metabolic plasticity under hypoxic and nutrient‐deprived conditions [69]. These metabolic changes correlate with smoking status, advanced tumor stage, metastasis, and poor survival. Tobacco smoke also contains advanced glycation end‐products (AGE) that can bind to proteins or disrupt specific glycosylation pathways of serum proteins in lung cancer patients. Cigarette smoke modifies mucin‐1 (MUC1) protein glycosylation, disrupting airway adherens junctions and promoting EMT, elevating risks for inflammation and metastasis [70]. Additionally, Mahmood et al. investigated EMT biomarkers in central and peripheral parts of NSCLC tumors and found that EGFR, S100A4, vimentin, and N‐cadherin expression was higher in tumor cells located at the peripheral leading edge of NSCLC when compared with centrally located tumor cells of the same subjects. They also found strong relationships between NSCLC EMT activity and small airway EMT activity in squamous cell carcinoma and adenocarcinoma samples [71]. The potential association between NSCLC and small airway involvement may also lie in the fact that peribronchiolar metaplasia and peribronchiolar fibrosis can often be observed as incidental findings in surgical lung resection samples [72].

Smoking‐associated NSCLC typically exhibits higher tumor mutational burden and increased programmed death‐ligand 1 (PD‐L1) expression, contributing to improved initial responses to immune checkpoint inhibitors, while persistent inflammation, oxidative stress, and enhanced DNA repair capacity may limit response durability and promote tumor resistance [73, 74]. Importantly, smoking‐driven molecular programs such as elevated tumor mutational burden, above‐mentioned PD‐L1 upregulation, KEAP1–Nr2 pathway activation, and above‐mentioned NF‐κB–PI3K–AKT signaling convergence represent actionable biomarkers and therapeutic vulnerabilities that may guide precision strategies in smoking‐related NSCLC [31, 35, 75, 76, 77, 78].

In addition to direct genotoxic and inflammatory effects, chronic cigarette smoking reshapes the lung tumor microenvironment through hypoxia‐driven and immune‐mediated mechanisms. Sustained smoke exposure promotes chronic tissue hypoxia, leading to activation of HIF‐1α‐dependent transcriptional programs that cooperate with NF‐κB and PI3K–AKT signaling to enhance angiogenesis, metabolic reprogramming, EMT, and resistance to therapy [7, 35]. Hypoxia‐associated signaling further amplifies glycolytic dependency and redox adaptation in smoking‐related NSCLC [79, 80]. Persistent inflammation further promotes the recruitment and polarization of tumor‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSCs), and dysfunctional neutrophils, fostering immunosuppression, angiogenesis, and ECM remodeling [50, 51]. Finally, several developmental signaling pathways including WNT/β‐catenin, NOTCH, and YAP/TAZ signaling have been implicated as downstream effectors of smoking‐induced inflammation and mechanical stress, contributing to lineage plasticity, stemness, and aggressive tumor phenotypes in NSCLC [81, 82, 83]. Although rarely acting as primary drivers, these pathways modulate tumor adaptability in the chronically smoking‐exposed lung. Taken together, these complex, overlapping and mutually amplifying processes ultimately support tumor progression and immune evasion.

3. Chronic Smoking Leads to Lung Tissue Destruction: Emphysema

COPD is the third leading cause of mortality worldwide [8, 84]. It is a very heterogeneous disease with many recognized phenotypes, of which chronic bronchitis and emphysema were the first to be described [8, 85, 86, 87, 88, 89]. Several other phenotypes have since been recognized, including eosinophilic COPD and frequent exacerbator phenotype, with manifestations often overlapping rather than being mutually exclusive [85, 86, 87, 90, 91, 92, 93]. The importance of recognizing COPD phenotypes in clinical practice is due to the fact that patients with different presentations and demographic characteristics have distinct outcomes, including the risk of acute exacerbations and mortality [22, 25, 86, 94, 95]. Additionally, the success of some therapeutic strategies, such as dupilumab for eosinophilic COPD or lung volume reduction for emphysema, is dependent on specific phenotypes [8, 96, 97, 98].

This review focuses on long term smoking‐induced tissue destruction leading to emphysema. However, there are other important environmental risk factors for emphysema (and COPD) development, including biomass fuel exposure, occupational exposures to organic and inorganic dusts and air pollution [8]. The etiopathogenesis of these factors is far less researched but likely involves similar mechanisms.

Emphysema is morphologically defined as irreversibly enlarged airspaces distal to and originating from the terminal bronchioles, with accompanying destruction of alveolar walls. Historically, an additional emphysema criterion was the absence of fibrosis; however, it has now been recognized that local fibrosis may be present [99]. COPD patients with emphysema have worse outcomes than those without emphysema, as supported by lower levels of forced expiratory volume at first second (FEV1) and increased FEV1 decline levels, lower body mass index, higher acute exacerbation rates, higher risk of lung cancer development, and higher mortality [20, 22, 23, 25, 100, 101].

Emphysema pathogenesis is very complex and not completely understood. It can be didactically divided into several intertwining axes which mutually interact and form vicious cycles that drive disease progression.

Chronic exposure to cigarette smoke leads to an increase in damage associated molecular pattern (DAMP) molecules in the airway epithelial cells and alveolar macrophages [102, 103]. Increased levels of several DAMPs have been found to be increased in the bronchoalveolar lavage fluid (BALF) of COPD patients, such as S100 proteins (namely S100A9), galectins (namely galectin‐3), defensins, and high‐mobility group box‐1 (HMGBP1) protein [102, 103]. These molecules attract and activate immune cells by binding to the pattern recognition receptors (PRRs), most famous being the toll‐like receptors (TLR) and receptor for advanced glycation end‐products (RAGE). RAGE ligands (such as HMGB1, S100A8, and LL‐37) were found to be increased in both BALF and serum of COPD patients in comparison to healthy smokers and nonsmokers [102, 103, 104, 105, 106]. Lower levels of soluble RAGE (sRAGE) have been proposed as a biomarker of emphysema [104, 105]. Namely, sRAGE likely acts as a decoy for the RAGE ligands and prevents the interaction with RAGE receptors and further RAGE signaling [103, 104, 105, 107]. Both TLR and RAGE induce the NFκB‐mediated release of proinflammatory cytokines which leads to macrophage activation and recruitment of neutrophils. Neutrophils and macrophages can then lead to further release of DAMPs and thus close the vicious circle and support the creation of a chronic inflammatory microenvironment [103, 104, 105, 107, 108]. Importantly, there is also an increase of CD8+ lymphocytes in the lungs of COPD patients, which contribute to persistent chronic inflammation. In addition, these cells also have elevated expression of granzymes and perforin, which is associated with programmed cell death [109, 110, 111].

Neutrophil degranulation leads to the release of neutrophil elastase and other proteolytic enzymes. These enzymes may degrade elastin directly, or act indirectly through the proteolytic activation of the macrophage elastase MMP12 and thus contribute to the lung extracellular matrix (ECM) destruction [110, 112, 113, 114, 115]. Additionally, neutrophils release neutrophil extracellular traps (NETs), which lead to the support of further proinflammatory milieu and ECM destruction [116, 117, 118].

The number of macrophages in the BALF and sputum of patients with COPD is markedly increased [119, 120]. Activated macrophages produce inflammatory mediators, including TNFα, IL‐8, and chemokines, as well as matrix metalloproteinases such as MMP‐2, ‐9, and ‐12. They also produce endogenous ROS. In healthy (nonsmoking) individuals, the majority of alveolar macrophages are in a non‐polarized state. In COPD, however, a dual polarization to M1 and M2 phenotypes has been observed [119, 120, 121, 122]. Namely, Eapen et al. found an increase of pro‐inflammatory M1 macrophage polarization and a relative decrease of M2 polarization in small airways of COPD, but found that luminal macrophages exerted an M2 profile, which was accompanied by the finding of the M2 cytokine profile of BALF of COPD patients [123]. M1 macrophages express inducible nitric oxide synthase (iNOS) and proinflammatory cytokines which drive chronic inflammation. In spite of the relative reduction of M2 polarization (in contrast to M1), M2 polarized macrophages also play an important role in the pathogenesis of COPD and emphysema. Cytokines such as IL‐4, IL‐13, IL‐10, and TGF‐β induce M2 polarization, which is linked to Th2 immune response pattern and is associated with tissue repair and remodeling in COPD. The distinct roles of M1 and M2 in the pathogenesis of COPD and emphysema are yet to be elucidated [122, 123, 124].

Elastin is an essential ECM protein which is responsible for the elastic features of the lungs (as well as other tissues such as blood vessels, skin, ligaments and cartilage). Proteolytic degradation of elastin (by enzymes such as matrix metalloproteinases, serine proteases and cysteine proteases) releases elastin‐derived peptides, termed elastokines, which promote angiogenesis, stimulate cell adhesion, chemotaxis, proliferation, further protease activation and apoptosis [110, 114, 115, 125, 126]. The role of elastin homeostasis is further highlighted in the fact that anti‐elastin antibodies have been detected in smoking‐induced emphysema [114, 126]. Low et al. found that these autoantibodies have the potential to induce T cell proliferation in the emphysema‐affected lungs [127]. These findings support the hypothesis of the autoimmune role in the pathogenesis of emphysema.

The primary hypothesis of emphysema development is the protease‐antiprotease imbalance. Namely, prolonged exposure to pathogenic factors, such as cigarette smoke, may induce an abnormal inflammation (as was discussed above) and increase the levels of proteases [110, 128, 129]. Additionally, the same irritants may lead to a reduction of antiproteases, thus aggravating this inequality. The increased levels of proteases are then responsible for the destruction of elastic fibers and cells [110, 125, 129, 130].

Another hypothesis of emphysema development deals with the dysregulation of the oxidant‐antioxidant axis: Exposure to cigarette smoke leads to the increase of exogenous oxidants in the lung [75, 110, 128]. In concert, due to the recruitment of inflammatory cells, the number of endogenous oxidative species also increases [75]. Reactive oxygen species can then further activate transcription of proinflammatory cytokines via the NF‐κB pathway and close another vicious cycle [75, 131]. In steady state, a counterbalance system of antioxidant network exists: the first line of defense against ROS is comprised of nonenzymatic molecules such as glutathione, vitamins C and E, and taurine. Additionally, several enzymes (such as superoxide dismutases, peroxiredoxins, thioredoxins, and glutaredoxins) act in concert with nonenzymatic antioxidants to maintain redox homeostasis [75, 128]. On the cellular level, in oxidative stress, nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is activated, which then enables the expression of genes such as NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1), and glutathione S‐transferase (GST), which are able to eliminate ROS after binding to the antioxidant response elements (ARE) [45, 75, 76, 131, 132, 133]. Namely, Nrf2 levels were found to be lower in mice with cigarette smoking‐induced emphysema, and Nrf2 knock‐outs were more susceptible to the development of emphysema [134]. Nrf2 levels were observed to be increased in the blood plasma of COPD patients [135, 136]. Additionally, NQO1, HO1, superoxide dismutase type 1, and thioredoxin reductase were found to be downregulated in COPD patients [136]. Our previous study found several enzymes responsible for the maintenance of redox homeostasis to be increased in the plasma of emphysema patients in comparison to healthy never smokers, which include peroxiredoxin‐1, ‐2, and ‐6, as well as glutaredoxin‐1 [128]. We found thioredoxin levels to be reduced both in blood plasma and induced sputum of COPD (both emphysema and non‐emphysema) and healthy smokers in comparison to healthy never‐smokers ([128]; induced sputum data not yet published). Mitochondrial dysfunction represents an additional important mechanism contributing to smoking‐induced lung injury [11, 137, 138]. Cigarette smoke exposure increases mitochondrial reactive oxygen species production and impairs mitochondrial quality control mechanisms, including mitophagy. These alterations lead to metabolic reprogramming, sustained oxidative stress, and altered cell survival signaling [11, 137, 139, 140, 141].

Various forms of programmed cell deaths are thought to contribute to COPD development, including apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and anoikis [110, 111, 128, 142, 143, 144, 145]. Direct induction of apoptosis of the pulmonary endothelial or epithelial cells in rodents is accompanied by emphysema. On the other hand, mice with abnormalities in apoptotic cell removal also tend to develop emphysema. The exact role of apoptosis and other programmed cell deaths is yet to be defined [105, 110, 125]. In recent years, anoikis has become of greater interest in the field of COPD pathogenesis. Anoikis is a form of programmed cell death that is triggered by the detachment of cells from the ECM or from the loss of cell–cell contact [128, 144, 146, 147]. Resistance to anoikis is the way cancer cells can achieve metastatic potential [146, 148, 149]. Chen et al. classified COPD patients with distinct anoikis patterns: pro‐anoikis and anti‐anoikis [147]. Those with an anti‐anoikis phenotype demonstrate more severe GOLD stages and higher smoking pack‐years levels. Chen et al. found that BMP4, galectin‐1, LRP1, and RBP1 are associated with anoikis [147]. In a recent study, Hu et al. developed a model for the prognosis, phenotyping, and progression of COPD based on small airway epithelium samples in which they analyzed genes based on anoikis resistance: They found that malic enzyme 1 (ME1), solute carrier family 2 member 1 (SLC2A1), and bone morphogenetic protein 4 (BMP4) (anoikis‐related biomarkers) were upregulated in COPD with a strong negative correlation with emphysema, a positive correlation with airway wall thickness, and an association with peribronchial immune cell infiltration [144]. Interestingly, based on our LC–MS data, we found the ME1 protein product (NADP‐dependent malic enzyme) to be increased in blood plasma in patients with emphysema in comparison to patients with COPD without emphysema, healthy smokers, and healthy never‐smokers [128].

Injury of elastic fibers in the ECM (i.e., elastin and its microfibrils, namely fibrillin) lead to the weaking of the structural integrity of small airways and alveolar septa (loss of alveolar septa scaffolding) and the impairment of tethers which normally ensure elastic recoil during expiration and prevention of alveolar overdistention and small airway collapse. Ultimately, there is a destruction of alveolar‐capillary cells and impairment of gas exchange [110, 115, 125, 129]. Disruption of mechanical forces and the nonuniform lung tissue damage leads to the generation of stress concentration zones and compensatory overexpansion, which leads to mechanical strain. Additionally, this disruption of mechanical forces also mediates intercellular signaling and likely contributes to disease pathogenesis [110].

The involvement of small airway disease in the pathogenesis of emphysema has become a subject of debate in recent years [147]. In their pathohistological analysis of small airways, Hogg et al. found that the progression of COPD in general was strongly associated with an increase in the volume of tissue in the wall and the accumulation of inflammatory mucous exudates in the lumen of small airways [150]. A growing body of evidence suggests that epithelial‐mesenchymal transformation (EMT) may also be involved in small airways of COPD patients, with the most recognized involvement of TGF‐β/Smad, Wnt/β‐catenin, PI3K/Akt, and NF‐κB signaling pathways [151, 152, 153, 154, 155]. In their CT‐based study, Diaz et al. found a reduced number of airways in lung tissue undergoing emphysematous destruction [156, 157]. Additionally, McDonough et al. found that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD [157]. Furthermore, Han et Hatt pose that therapeutic interventions on small airway disease in early COPD might be effective in slowing emphysema progression [147]. On the other hand, even though it has been believed that most emphysema tends to arise from small airway disease damage, recent findings suggest that an important driver of emphysema progression may be the mechanical stress experienced by normal lung tissue which is adjacent to the existing emphysema (similarly to the zone of penumbra in the process of an infarction) [158]. Bhatt et al. conducted a CT‐scan‐based study which enrolled almost 5000 participants in which they found that new emphysema arises from the areas of high mechanically affected lung (MAL) in a substantially higher proportion than areas of small airway disease. However, it is worth noting that patients had to have at least 5% of emphysema on chest CT scans in order to be included in the analysis [147, 158]. Additionally, Verheyen et al. found no differences in the number of terminal bronchioles, transitional bronchioles, airway wall thickness, and airway diameter between the explanted lungs of COPD patients with and without emphysema [159]. The true anatomical origin of emphysema and many unknown questions in its pathogenesis are yet to be elucidated.

4. Chronic Smoking Leads to Aberrant Healing: Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is (one of) the most common fibrosing diffuse parenchymal lung diseases [160]. Usual interstitial pneumonia (UIP), the pathological hallmark pattern of IPF, consists of subpleural and paraseptal predominant interstitial fibrosis with both temporal and spatial heterogeneity, abrupt transition of normal to fibrotic lung, fibroblastic foci and honeycombing (clustered cystic airspaces of consistent diameter with thick, well‐defined walls) [161, 162]. It is important to note that in up to 25% of UIP/IPF patients, areas of nonspecific interstitial pneumonia (NSIP) have been described [161, 163]. It is also worth mentioning the group of interstitial pneumonias that have previously been classified as smoking‐related in the now‐outdated 2013 classification update, including respiratory bronchiolitis interstitial lung disease (RB‐ILD) and desquamative interstitial pneumonia (DIP) (renamed to alveolar macrophage pneumonia, AMP in the 2025 update); however, they are beyond the scope of this review [161, 164].

Cigarette smoking is the most recognized risk factor and is consistently associated with a higher likelihood of IPF [165, 166, 167]. The main pathophysiological paradigm of IPF used to emphasize chronic inflammation; however, newer paradigms define IPF as an epithelial‐driven, fibroproliferative disease [168]. The fact that chronic inflammation is likely not the main driver of IPF pathogenesis was also reflected in the results of the PANTHER‐IPF trial in which an increased risk of death and hospitalization were observed in those treated with prednisone, azathioprine, and N‐acetylcysteine compared to the placebo arm [169, 170].

Smoking likely acts as a harmful factor to alveolar epithelial cells type II (AEC2), which are the main type of cells implicated in IPF pathophysiology [171, 172]. Recent evidence suggests that important pathogenic mechanisms include repetitive injury to alveolar epithelial cells which may cause their aberrant activation and increased release of profibrotic mediators, as well as supporting EMT, causing alveolar cells to acquire fibroblast‐like phenotypes, in addition to endoplasmatic reticulum (ER) stress and oxidative stress [167, 172].

An important profibrotic mediator is TGF‐β1, as it is a key activator of fibroblast to myofibroblast differentiation and regulates numerous genes involved in the ECM synthesis and accumulation [172, 173]. Cigarette smoke extract (CSE) was found to induce a fibroblast‐like phenotype in human lung epithelial cell lines, as well as a significant overexpression of genes involved in EMT and profibrotic genes. Additionally, these cells also showed dysregulation of TGF‐β and Wnt signaling pathways and increased secretion of activated TGF‐β1 [172]. Several studies found an aberrant Wnt signature in IPF and experimental lung fibrosis. Importantly, aberrant Wnt/β‐catenin may lead to increased cellular senescence and fibrotic marker expression in epithelial cells, underlining its potential importance in IPF pathogenesis [174]. Activated TGF‐β1 contributes to IPF pathogenesis by inducing expression of ECM components, such as collagens, fibronectin, α‐smooth muscle actin (α‐SMA), vimentin, and MMP‐9 from fibroblasts [175]. TGF‐β1 is also important in contributing to EMT, which has long been recognized as one of the key mechanisms involved in fibrosis in IPF. Furthermore, TGF‐β1 activates signaling pathways, such as Smad and ERK/MAP kinases (through type I and type II TGF receptors), which causes stimulation of Snail and Twist transcription (fibroblast transcription factors), which in turn inhibit production of endothelial markers and activate expression of mesenchymal markers [176].

Nicotine, one of the main ingredients of tobacco smoke, has an angiogenic effect. This effect is partly mediated by stimulation of growth factors and their receptors, such as fibroblast growth factor (FGF), platelet‐derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) [177, 178, 179]. Interestingly, one of the few antifibrotic drugs available for IPF treatment (nintedanib) works by inhibition of these receptors, which implies their potential pathogenic role in IPF development [180]. Ebrahimpour et al. found that nicotine upregulates the expression of inflammatory cytokine genes targeted by miR‐24 (members of the TNF receptor superfamily, IL2RB, IL17B, IL21, bone morphogenetic proteins, etc.), growth factors (FGF, PDGF, FGF, and VEGF), fibroblast proliferation, collagen release, and expression of myofibroblast markers (α‐SMA and type I collagen) in explanted lung tissue or lung cells [177].

Accumulating evidence suggests that smoking‐related increased oxidative stress might promote disease progression in IPF patients through stimulation of ROS, endoplasmic reticulum (ER) stress and production of NADPH oxidases, especially NADPH oxidase‐4 (NOX4), by both inflammatory and lung cells [176, 181]. Oxidative stress, as well as ROS‐activated TGF‐β1 signaling, downregulate expression of Nrf‐2, an important antioxidant transcription factor, which is reflected in a decreased expression of a variety of antioxidant enzymes, such as catalase and superoxide dismutase 1 and 2 [175]. An additional significant impact of oxidative stress is that it promotes release of proinflammatory mediators, such as CSE‐induced IL‐8. Early inflammatory signaling further amplifies recruitment and activation of inflammatory cells through mediators such as intercellular adhesion molecule 1 (ICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1), and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). The thereby caused persistent inflammation then promotes profibrotic pathways (most notably the aforementioned TGF‐β1), which drive fibroblast proliferation and myofibroblast differentiation [175].

Another mechanism through which smoking seems to contribute to IPF pathogenesis is ER stress, which promotes fibroblast‐to‐myofibroblast differentiation, a prominent feature of IPF [180, 182]. In response to ER stress, a signaling cascade named the unfolded protein response (UPR) is activated. As misfolded or unfolded proteins accumulate in the ER, its main purpose is to restore protein‐folding balance and maintain cell survival. Song et al. demonstrated the connection between smoking‐associated ER stress and fibroblast differentiation in vitro, as they showed CSE‐treated human embryonic lung fibroblasts showed increased expression of ER stress/UPR proteins (GRP78, IRE1, XBP‐1, and ATF6) as well as α‐SMA, suggesting ER stress and promotion of myofibroblast differentiation [182]. A signature of chronic cell stress response and UPR markers was also identified by comparative proteomics in IPF lung tissue [180]. Chronic exposure to smoke‐induced injury can also cause UPR to shift toward ER‐stress induced apoptosis of the AEC2, mediated at least partly through induction of CHOP [180].

Cellular senescence is an additional important pathophysiological mechanism through which smoking contributes to IPF. Senescent cells accumulate in fibrotic lungs and play a vital role in the pathogenesis of pulmonary fibrosis [6, 183]. Importantly, senescent cells acquire a distinct, senescence‐associated secretory phenotype, causing them to release profibrotic mediators [180, 184]. Specifically, senescent AEC2 secrete proinflammatory and profibrotic factors, which promote fibroblast proliferation, activation, migration, and collagen deposition [6]. Namely, Shi et al. found that smoking downregulates protection of telomeres 1 (POT1), essential for regulating and maintaining telomere length, by promoting DNA methyltransferase (DNMT) expression. This may activate phosphorylation and activation of ATM/ATR and p53 through DNA damage, which causes senescence of AEC2 cells [6].

An increasingly recognized feature of IPF is the involvement of small airways, whose epithelial cell populations have significant roles in disease development and fibrogenesis [181, 185, 186, 187, 188, 189, 190]. The small airway dysfunction was associated with cigarette smoking and was evidenced by airway distortion, metaplasia, airway obliteration, airway inflammation and mucous within the airways [188, 191]. Impulse oscimetry and spirometry‐based studies have also recognized functional small‐airway dysfunction in IPF patients [185, 188, 189]. Similar to its roles in COPD, MUC5B has also been implicated in IPF. The single nucleotide polymorphism (SNP) mutation of MUC5B promoter (rs35705950) causes MUC5B overproduction in the bronchiolar epithelial cells, leading to mucus oversecretion, airway distortion and occlusion [187, 188]. This SNP has been consistently recognized as a risk factor for IPF development [191, 192]. However, the role of this polymorphism in terms of IPF prognosis in patients on antifibrotic therapy is not clear: while Biondini et al. found a potential signal, Lewandowska et al. did not [192, 193].

The entirety of molecular pathways through which smoking impacts IPF pathogenesis is still unknown. However, a substantial body of existing evidence points to a complex, multifactorial, and interweaving set of mechanisms, including AEC injury, TGF‐β1‐related profibrotic signaling, ER stress, and cellular senescence, all leading to fibrosis development – the hallmark of IPF. These mechanisms need further study, especially in the setting of limited available therapeutic options in IPF treatment and poor disease prognosis [194].

5. Conclusion

Chronic cigarette smoking represents one of the most important environmental drivers of lung disease, contributing to the development of many distinct pathological entities [10, 32, 40, 43, 195, 196]. We aimed to highlight the harmful impact of chronic cigarette smoke exposure on the development of NSCLC, emphysema, and IPF. Although these conditions differ markedly in their clinical presentation and pathological features, accumulating evidence indicates that there are common mechanisms which likely arise from long‐term exposure to cigarette smoke (Figure 1).

FIGURE 1.

Graphic showing common chronic smoking‐associated pathways and mechanisms which have been highlighted throughout the text as potential important pathogenic mechanisms in NSCLC, emphysema or IPF. Only pathways which are shared by 2 of 3 or all 3 entities are shown. Pathways are connected through lines with the associated disease: NSCLC (black lines), emphysema (brown dashed lines), and IPF (red lines). Created in BioRender. Hrkač (2026) https://BioRender.com/yomfxdn.

Epithelial cells present the common central “playing field” crucial for the pathogenesis of NSCLC, emphysema, and IPF. Chronic epithelial injury, which initiates a cascade of interconnected biological responses involving oxidative stress, persistent inflammation, mitochondrial dysfunction, and dysregulated immune signaling. These events promote significant alterations in tissue homeostasis, including ECM remodeling, abnormal cell survival, and programmed cellular death, as well as the emergence of cellular senescence.

Together, these mechanisms reshape the lung microenvironment and influence the trajectory of disease development. Broadly, the (im)balance between a plethora of interconnected molecular processes appears to determine the predominant pathological outcome. Integrative insight into shared and disease‐specific molecular patterns in future research may aid in the identification of novel biomarkers, improve risk stratification, and guide the development of targeted therapeutic strategies. This review is not meant to represent an exhaustive reference of pathophysiologic processes involved in the pathogenesis of these diseases, but to illustrate the common features and specific differences among the selected disease processes.

Finally, it is important to highlight that these diseases may affect one another. One such example was highlighted by Houghton in the fact that enhanced Th1‐mediated immunity and CD8+ cellular activation in patients with COPD and lung cancer may explain the fact that COPD patients display prolonged survival with immune checkpoint inhibitor therapy [197]. Given the persistent global burden of tobacco use, further research into the interconnected molecular consequences of cigarette smoke exposure remains essential for advancing both preventive and therapeutic approaches in pulmonary medicine.

Author Contributions

Stela Hrkač: writing – original draft, conceptualization, data curation, investigation, visualization. Grgur Salai: writing – original draft, conceptualization, data curation, investigation. Tomo Svaguša: writing – review and editing, data curation, investigation. Joško Mitrović: writing – review and editing, data curation, investigation. Ruđer Novak: writing – original draft, conceptualization, data curation, investigation. Lovorka Grgurević: conceptualization, supervision, writing – original draft, data curation, investigation.

Funding

The authors have nothing to report.

Ethics Statement

This work was not subjected to the Ethics Committee review.

Conflicts of Interest

Parts of the text regarding emphysema pathogenesis were translated from Grgur Salai's doctoral thesis introduction section (not yet published). The authors declare no immediate conflicts of interest. Lovorka Grgurević declares no conflict of interest. Stela Hrkač received support for attending scientific congresses from Boehringer Ingelheim Croatia and Octapharma AG. Ruđer Novak declares no conflict of interest. Grgur Salai received speaker fees from Astra Zeneca Croatia, Berlin Chemie Menarini Croatia, Alkaloid Ltd. and Providens Ltd., as well as travel support for attending scientific congresses from Boehringer Ingelheim Croatia, Berlin Chemie Menarini, Viatris Croatia and Providens Ltd. Joško Mitrović declares no conflict of interest. Tomo Svaguša declares no conflict of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.