Autophagy as a Redox Rheostat Linking Cigarette Smoke, Electronic Cigarettes, and Nicotine Exposure to Lung Development, Disease, and Interorgan Communication

Abstract

Autophagy is a central cellular quality-control pathway that maintains metabolic and proteostatic homeostasis by degrading damaged organelles and proteins. In the lung, autophagy contributes to normal development, epithelial integrity, mitochondrial quality control, and immune regulation. Emerging evidence indicates that environmental exposures such as cigarette smoke (CS), electronic cigarette (EC) aerosols, and nicotine profoundly disrupt these processes, contributing to both chronic lung disease and developmental programming of respiratory pathology. In this review, we propose a unifying framework in which autophagy functions as a redox-modulated rheostat that integrates oxidative, metabolic, and epigenetic stress signals triggered by smoke and nicotine exposure. Under physiological conditions, autophagy mitigates oxidative stress by removing dysfunctional mitochondria and maintaining proteostasis. However, chronic exposure to CS or EC aerosols generates excessive reactive oxygen species, impairs lysosomal degradation, and disrupts mitochondrial quality control, shifting autophagy from an adaptive protective response to a maladaptive driver of epithelial injury, inflammation, and tissue remodeling. Integrating experimental and clinical evidence, we identify four mechanistic axes underlying smoke-induced autophagy dysregulation: lysosomal dysfunction with TFEB suppression, mitochondrial redox amplification, disruption of selective autophagy pathways (including mitophagy, ER-phagy, xenophagy, and lipophagy), and immune polarization associated with inflammasome activation and cellular senescence. Importantly, maternal smoke and EC exposure similarly perturb autophagy in the placenta and fetal lung, altering developmental trajectories and increasing susceptibility to asthma and chronic lung disease. Viewing autophagy as a dynamic, redox-sensitive rheostat highlights new therapeutic opportunities to restore autophagic flux, lysosomal competence, and mitochondrial quality control in smoke- and nicotine-related lung disease.

1 |. Introduction

Autophagy is a cellular housekeeping pathway that recycles dysfunctional organelles and proteins, helping cells maintain metabolic balance during development and under nutrient stress. It has a role in removing damaged organelles, such as mitochondria and the endoplasmic reticulum, and in clearing intracellular pathogens. In other words, autophagy acts as a cellular recycling factory that promotes energy efficiency by generating ATP and protects the cell by eliminating nonfunctional, damaged proteins and organelles (Glick et al. 2010). While the lung is the primary portal for smoke and nicotine entry, these exposures trigger a systemic inflammatory cascade that extends far beyond the pulmonary compartment. Autophagy-mediated stress signals and pro-inflammatory cytokines (SASP) generated in the lung enter the systemic circulation, facilitating interorgan communication that impacts cardiovascular, metabolic, and placental health. Thus, the autophagy rheostat serves not only as a local regulator of lung proteostasis but also as a systemic signaling hub that programs disease susceptibility in distant organs.

1.1 |. Autophagy in Lung Development and Lung-Related Diseases

Autophagy has been reported to participate in the normal development of many organs, including the lung, where it is a key regulator of airway branching and terminal sacculi formation (Yeganeh et al. 2019). It has been found that activation of epithelial autophagy in the developing mouse lung results from AMPK activation; inhibition of AMPK-mediated autophagy reduces lung branching in vitro. Autophagic activity diminishes with age in various species, although its fundamental activity remains throughout the lifespan. Dysregulation of autophagy has been linked to the development of pulmonary diseases associated with aging, including acute lung injury, chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis (Zhang et al. 2022; Liao et al. 2019).

Autophagy is generally considered a survival mechanism, and its deregulation has been linked to cell death (Glick et al. 2010). In chronic lung diseases, loss or insufficiency of autophagy leads to lung inflammation and damage, suggesting a protective role for autophagy. However, under extreme conditions, this homeostatic cellular process may become impaired and unable to handle excessive autophagic targets, resulting in cell death and tissue damage (Ornatowski et al. 2020). Specifically, cigarette smoke (CS), well known to initiate and exacerbate multiple lung diseases (Wang et al. 2018), increases autophagosome formation and disrupts the autophagy–mitophagy balance, driving epithelial apoptosis (Ballard et al. 2010). Similarly, maternal smoking during pregnancy perturbs autophagy in both placenta and fetal lung, leading to maladaptive autophagic flux and impaired trophoblast and epithelial cell differentiation and altered immune function, resulting in abnormal alveolarization, heightened inflammation, and long-term susceptibility to asthma and COPD in the offspring (McEvoy and Spindel 2017; Thacher et al. 2018; Künstle et al. 2024b; Hollams et al. 2014). Despite these known associations, the mechanisms linking autophagy to lung diseases and altered lung development remain poorly understood and understudied.

Given its sensitivity to redox status, energy stress, and xenobiotic load, autophagy is uniquely positioned to integrate pulmonary pathological responses triggered by CS and vaping aerosols. In this review, we propose that autophagy acts as a redox- modulated rheostat that integrates oxidative, metabolic, and epigenetic stress signals across different lung compartments and developmental stages.

2 |. Cigarette Smoke, E-Cigarettes, and Nicotine: Autophagy as a Redox Rheostat in Lung Pathology

Although numerous direct and indirect effects of CS constituents, e-cigarettes (ECs), and nicotine on the lungs have been described, autophagy is now recognized as a central mechanistic hub underlying their influence on lung development, injury, and repair. These exposures impose a persistent oxidant and xenobiotic burden, initially activating autophagy as a protective stress response. Autophagy restores metabolic balance during oxidative and nutrient stress by removing damaged organelles, especially dysfunctional mitochondria, and thereby reducing the ROS burden (Mathew et al. 2009; Filomeni et al. 2015). Because ROS signaling intersects with autophagy at multiple levels (mitochondrial quality control, ER stress, AMPK/mTOR, and lysosomal function), these mechanisms are described once here and referenced throughout subsequent sections.

Under physiological conditions, mitochondria generate minimal ROS; however, basal ROS levels play essential roles in regulating proliferation, growth factor signaling, immune responses, differentiation, and autophagy itself. Hypoxia is also a potent modulator of mitochondrial ROS production and the activation of autophagy (Wang et al. 2018; Sena and Chandel 2012).

When the oxidant or xenobiotic burden becomes chronic or excessive, autophagy becomes maladaptive, leading to impaired autophagic flux, mitochondrial injury, and proteostasis collapse (Figure 1). The resulting accumulation of dysfunctional mitochondria and protein aggregates drives apoptosis, senescence, inflammation, and tissue remodeling. In this way, autophagy functions as a redox rheostat, determining cellular outcomes along the continuum from adaptation to injury.

FIGURE 1 |.

Cigarette smoke, e-cigarette, and nicotine exposure disrupt autophagy and promote mitochondrial injury. Under physiologic conditions, balanced ROS levels, AMPK–mTOR signaling, and efficient autophagic flux maintain cellular homeostasis. Exposure to cigarette smoke, e-cigarette aerosols, or nicotine increases oxidative stress and impairs autophagy, leading to mitochondrial injury and elevated ROS production. Chronic exposure further suppresses lysosomal function and autophagic flux, promoting aggresome accumulation. These alterations drive a continuum of cellular responses ranging from adaptive and compensatory changes to maladaptive and pathogenic outcomes.

2.1 |. Cigarette Smoke: Oxidative Stress and Autophagy Dysregulation

Cigarette smoke contains more than 7000 chemicals and a massive oxidant burden, driving mitochondrial ROS production, lipid peroxidation, protein adduct formation, and endoplasmic reticulum stress in bronchial and alveolar epithelial cells. These insults robustly induce autophagosome formation, LC 3-II accumulation, and p62 turnover, while simultaneously dysregulating mitophagy and impairing lysosomal function (Ahmad et al. 2015). Importantly, increases in LC 3-II or in the number of autophagosomes do not necessarily indicate productive autophagy. These markers reflect the quantity of autophagosomes but cannot distinguish whether autophagosomes are successfully degraded. In CS-exposed lung tissue, impaired autophagosome–lysosome fusion frequently results in LC3-II accumulation despite reduced flux. Thus, it is the quality and completion of autophagic flux, rather than autophagosome load alone, that determines whether autophagy is protective or pathogenic in the smoke-exposed lung.

Chronic CS exposure produces two maladaptive autophagy phenotypes: (1) excessive autophagy/mitophagy, contributing to epithelial apoptosis and emphysematous destruction (Ballard et al. 2010), and (2) impaired autophagic flux, leading to p62-positive aggregates and proteostasis failure, a hallmark of COPD lungs. CS-induced protein aggregates (“aggresomes”) not only reflect failed proteostasis but also drive inflammatory signaling and cellular senescence, accelerating lung aging and functional decline. Notably, aggresome burden has emerged as a prognostic biomarker that correlates with COPD-emphysema severity (Vij et al. 2018). Thus, CS fundamentally disrupts the lung’s intrinsic “self-cleaning” machinery, promoting progressive tissue injury.

Mechanistically, CS activates multiple redox-sensitive signaling pathways, including RAGE–NF-κB, ERK1/2, and PI3K/Akt, and induces key autophagy regulators, including OSGIN1 (Pallet 2017), ATG16L1, and follistatin-like protein 1 (FSTL1) (Liu et al. 2021). These pathways integrate ROS signals into cell death, inflammatory, and remodeling responses. Transcriptomic studies show that OSGIN1 is among the most strongly upregulated genes in the airway epithelium of smokers, where it enhances autophagic flux and promotes apoptosis (Pallet 2017). Similarly, CS-induced elevation of FSTL1, typically an embryogenic regulatory protein, augments autophagy and drives airway inflammation and structural remodeling; inhibition of autophagy with 3-methyladenine (3-MA) attenuates these effects, underscoring the pathogenic contribution of autophagy activation in COPD development (Liu et al. 2021).

Additional evidence indicates that CS activates autophagy through mTOR inhibition, exacerbating lung injury in experimental models (Wang et al. 2018). Collectively, these autophagy abnormalities contribute to hallmark structural and immunologic outcomes of chronic smoking, including emphysema, small-airway fibrosis, impaired host defense, and increased susceptibility to carcinogenesis (Zhao et al. 2015).

3 |. Electronic Cigarettes: Combustion-Free but Not Autophagy-Neutral

Electronic cigarette aerosols lack combustion products but contain nicotine, carbonyls, metals, volatile organic compounds, and flavoring aldehydes, each of which can induce oxidative and electrophilic stress (Lee et al. 2017).

Multiple studies now show that EC aerosols alter canonical autophagy pathways. For example, EC aerosol induces autophagy (LC3-II upregulation) in human bronchial epithelial cells without triggering apoptosis (Shivalingappa et al. 2016); EC vapor exposure triggers autophagy activation and mitochondrial stress in human lung fibroblasts (Lerner et al. 2016), and flavoring aldehydes (diacetyl, cinnamaldehyde) disrupt autophagic flux and produce toxic autophagosome accumulation (Cox et al. 2024).

In vivo, chronic EC exposure impairs lung autophagic flux, increases inflammatory cytokines, and disrupts mitochondrial quality control (Garcia-Arcos et al. 2016). Clinically, EC users demonstrate airway epithelial gene signatures consistent with oxidative stress, proteostatic disturbance, and impaired host defense (Martin et al. 2016). These mechanisms have been implicated in EC or Vaping Product Use-Associated Lung Injury (EVALI), in which lipid-laden macrophages, ROS-driven cytotoxicity, and autophagy impairment are prominent (Belok et al. 2020).

Maternal EC exposure further dysregulates autophagy in the fetal lung and pulmonary vasculature: a 2023 study reported ATG5-dependent “aberrant autophagy” that mediates pulmonary hypertension in EC-exposed offspring (Chen et al. 2025).

4 |. Nicotine: A Shared Autophagy-Modulating Denominator

Nicotine itself is a potent modulator of autophagy and a shared constituent of both CS and EC aerosols. In human bronchial epithelial cells and murine lungs, nicotine generates mitochondrial ROS and activates early autophagy, impairs autophagic flux and lysosomal degradation at higher exposures, and accumulates dysfunctional mitochondria and p62 aggregates, leading to apoptosis and senescence. Additionally, it alters cytoskeletal dynamics and reduces wound repair via autophagy dysregulation (Bodas et al. 2016).

Mechanistically, nicotine signals through nAChRs, Ca²⁺ influx, oxidative stress, and ER–mitochondrial stress pathways converging on AMPK-mTOR-ULK1 regulation of autophagy (Bodas et al. 2016). Importantly, antioxidant treatment and autophagy-restoring compounds (e.g., resveratrol) attenuate nicotine-induced epithelial apoptosis (Liu et al. 2018).

5 |. Mechanistic Themes: Four Integrated Axes of Autophagy Dysregulation

Integrating experimental and clinical data across CS, EC, and nicotine exposure reveals four conserved mechanistic axes through which autophagy functions as a redox–immune rheostat in the lung.

• 1Lysosomal Dysfunction and TFEB Suppression: Failure of Autophagic Completion. A central abnormality across CS and EC exposure is impaired lysosomal competence. Cigarette smoke inhibits TFEB nuclear translocation, preventing induction of lysosomal biogenesis genes (Xu et al. 2023; Rajendrasozhan et al. 2017). Although autophagosome formation may initially increase, reduced lysosomal acidification and defective autophagosome–lysosome fusion impair the completion of flux (Ballard et al. 2010). This produces p62 accumulation, aggresome formation, and sustained inflammatory signaling. Thus, the pathological shift lies not in autophagy initiation per se, but in defective degradation capacity.
• 2Mitochondrial Quality Control and Redox Escalation. Excess oxidative and ER stress activate AMPK and suppress mTOR, triggering autophagy induction. However, chronic exposure perturbs mitophagy pathways (PINK1/ Parkin), resulting in either excessive mitochondrial turnover or accumulation of ROS-generating, dysfunctional mitochondria (Ballard et al. 2010; Nakahira et al. 2011). In immune cells, defective mitochondrial clearance amplifies inflammasome activation and IL-1β/IL-18 production, linking redox imbalance directly to inflammatory escalation (Nakahira et al. 2011; Pietrocola et al. 2014). This mitochondrial–redox amplification loop represents a core rheostat mechanism converting adaptive autophagy into pathogenic signaling.
• 3Selective Autophagy Module Disruption and Proteostasis Collapse (Figure 2). Smoke and vaping aerosols do not globally activate or inhibit autophagy; rather, they selectively perturb multiple organelle-specific pathways. In addition to mitophagy, ER-phagy becomes insufficient under an overwhelming unfolded protein load (Shivalingappa et al. 2016; Baimei et al., n.d.). Xenophagy impairment weakens host defense (Xie and Meijer 2024) while lipophagy dysregulation contributes to lipid-laden macrophage formation in EVALI (Maddock et al. 2019; Ghosh et al. 2021).

FIGURE 2 |.

Disruption of selective autophagy pathways by cigarette smoke, e-cigarette, and nicotine exposure promotes mitochondrial injury and airway remodeling. Selective autophagy pathways, including mitophagy, ER-phagy, xenophagy, and lipophagy, normally maintain cellular proteostasis through the autophagy–proteasome axis. Exposure to cigarette smoke, e-cigarette aerosols, or nicotine activates RAGE signaling and downstream NF-κB, PI3K/Akt, and ERK pathways, leading to dysregulation of autophagy-related mediators such as OSGIN1 and the BECN1 (ATG6)/VPS34–ATG7 complex. Impaired autophagic flux results in mitochondrial injury and ROS accumulation, contributing to dysfunctional mitophagy, lysosomal impairment, inflammatory responses, and ultimately airway remodeling.

Concurrent proteasome inhibition synergizes with defective autophagy, promoting accumulation of ubiquitin–p62 aggregates and epithelial–mesenchymal transition (Wang et al. 2019; Jiang et al. 2018). Collectively, selective module failure culminates in proteostasis collapse and tissue remodeling.

• 4Immune Polarization, Senescence, and Barrier Dysfunction (Figure 3). Autophagy intersects directly with immune regulation. It governs antigen presentation, particularly via MHC class II–dependent pathways (McHeyzer-Williams et al. 2012), restrains inflammasome activation, and modulates cytokine homeostasis. When autophagy becomes insufficient, myeloid and CD11c⁺ antigen-presenting cells exhibit enhanced IL-1β/IL-23 production and Th2/Th17 polarization (Lee et al. 2010). Accumulated cellular damage promotes senescence and pro-inflammatory SASP (Akhtari et al. 2024), amplifying chronic inflammation. Thus, autophagy dysfunction shifts the lung immune microenvironment from tolerance toward persistent inflammatory activation. These compartment-specific immune consequences are summarized in Figure 3.

FIGURE 3 |.

Oxidative stress–driven epithelial injury and immune dysregulation promote chronic lung inflammation and disease progression. Excessive accumulation of reactive oxygen species (ROS) in airway epithelial cells leads to barrier dysfunction, apoptosis, cellular senescence, and the release of senescence-associated secretory phenotype (SASP) factors. These changes activate CD11C⁺ myeloid cells and inflammasome signaling, increasing the production of IL-1β, IL-18, and IL-23, which promote Th2 and Th17 immune responses. Th2 cytokines (IL-4, IL-5, IL-9, IL-13) and Th17 cytokines (IL-17, IL-22) contribute to cytokine dysregulation, metabolic alterations, and immune imbalance. In addition to driving local airway hyperresponsiveness (AHR) and fibrosis, these epithelial and immune alterations release systemic factors that propagate oxidative stress to the cardiovascular, renal, and gastrointestinal systems, establishing the lung as a central hub for smoke-induced interorgan disease progression.

Together, these four axes, lysosomal failure, mitochondrial redox escalation, selective module disruption, and immune polarization, define the mechanistic framework by which autophagy operates as a redox-modulated rheostat in smoke- and nicotine-exposed lungs.

6 |. Autophagy as a Regulator of Lung Immune Cell Function

The lung is constantly exposed to the external environment; therefore, it must maintain immune tolerance to avoid over-reacting to non-pathogenic stimuli (Kanayama et al. 2015). Autophagy plays a critical role in immune regulation, immune cell metabolism, cytokine production, and the resolution of inflammation (O’Neill and Pearce 2016). Autophagy in pulmonary myeloid cells maintains low environmental microbial loads in the lungs and limits mitochondrial ROS production (Pietrocola et al. 2014; Kanayama et al. 2015). It inhibits excessive response to TLR4 ligands in alveolar macrophages. Hence, autophagy in alveolar macrophages is vital for preventing spontaneous pulmonary inflammation (Kanayama et al. 2015). Nicotine and smoking trigger the inflammasome pathway, leading to an elevation of mitochondrial ROS levels and inflammatory mediator production, which promote airway inflammation and disrupt tissue repair (Huot-Marchand et al. 2022).

6.1 |. Roles of Autophagy Within Lung Immune Compartments

There is a clear cell-type dependence on the immunologic consequences of autophagy dysfunction. In lymphoid cells, including T cells, B cells, and innate lymphoid cells, autophagy is critical for maintaining cell survival, metabolism, and cytokine production. Autophagy deficiency disrupts cytokine production and immune function (Pua et al. 2009; Chen et al. 2014). Similarly, autophagy in myeloid cells is essential for normal lung homeostasis. In the absence of autophagy in myeloid cells, inflammasome activation leads to a spontaneous sterile inflammatory response in the lung. This process was largely mediated by IL-18 production, which plays a major role in promoting lung inflammation (Abdel Fattah et al. 2015). Similarly, impaired autophagy in myeloid antigenpresenting cells (APCs) led to mitochondrial dysfunction, enhanced inflammasome activation, increased neutrophil recruitment, and Th17-skewed inflammatory responses (Zhong et al. 2016). Autophagy in immune cells also decreases with age, and immunosenescence is implicated in the development of age-related lung diseases (Zhang et al. 2022).

6.2 |. Autophagy Induction in CD11c⁺ Antigen-Presenting Cells as a Therapeutic Strategy for Inflammation and Injury

CD11c + pulmonary macrophages are involved in antigen presentation and T helper cell polarization. They also contribute to airway immune programming triggered by environmental exposures (Plantinga et al. 2013; Guilliams et al. 2013). Some studies demonstrated that a lack of autophagy in CD11c + APCs enhanced lung inflammation in a model of virus-induced acute respiratory distress syndrome (ARDS). Additionally, a deletion of Atg5, an essential autophagy protein, in CD11c + APCs increased lung inflammation and airway hyperreactivity (AHR) in a mouse model of asthma. Finally, induction of autophagy in CD11c + APCs alleviated inflammation and injury (Quach et al. 2023). It has been shown that autophagy deficiency in CD11c + cells promotes type 2 and type 17 immune responses in experimental airway disease models (Lee et al. 2010; Suzuki et al. 2016; Kinsella et al. 2023). Moreover, a study showed that a lack of autophagy in pulmonary CD11c + cells augments neutrophilic lung inflammation by promoting IL-17A secretion by T cells. In other words, the lack of autophagy in DCs induces Th17 polarization through elevated production of IL-1 and IL-23 (Suzuki et al. 2016). Cigarette smoke and nicotine impair autophagic flux, and CD11c + APCs are particularly subject to autophagy-dependent dysfunction (Monick et al. 2010).

These context-dependent effects highlight how smoke-induced disruption of autophagy might alter immune function across cellular compartments, aggravating inflammatory responses while impairing regulatory mechanisms and tissue repair.

7 |. Integrative Perspective: Autophagy Functions as a Redox–Immune Rheostat in the Lung

As discussed here, autophagy plays dual roles in the lungs, mediating both cellular degradation pathways and immune rheostat functions that integrate environmental exposures with immune and developmental processes. Exposure to ecigarettes, cigarette smoke, or nicotine changes cell redox balance, lysosomal function, mitochondrial quality control, and autophagic flux (Monick et al. 2010; Lam et al. 2013). Given that autophagy influences antigen presentation, cytokine production, and metabolic efficiency in lung-resident immune cells, autophagic alterations affect immune polarization, inflammation, and overall disease susceptibility (Bronietzki et al. 2015; Germic et al. 2019). Redox-sensitive autophagy pathways are established during fetal and early life development, when the immune system is formed and shapes how a person responds to environmental stressors throughout life (Levine and Kroemer 2019; Kuma et al. 2004). This perspective points to smoke and nicotine-induced lung disease as a condition driven by dysregulated autophagy rather than a simple loss of autophagic activity. In this context, restoring balance between autophagy and redox homeostasis becomes a main therapeutic priority.

8 |. The Lung as a Systemic Signaling Hub

8.1 |. Interorgan Propagation of Autophagy-Derived Stress Signals

The dysregulation of autophagy in the lungs does not remain localized; rather, it catalyzes systemic pathology. When the autophagic rheostat in the airway epithelium and alveolar macrophages shifts toward a maladaptive state, the resulting accumulation of ROS and p62-positive aggregates triggers the release of senescence-associated secretory phenotype (SASP) factors and pro-inflammatory cytokines into the systemic circulation (Cha et al. 2023). These lung-derived mediators, specifically IL-1β, IL-6, and TNF-α, facilitate a pathogenic “interorgan dialogue” (Müller and di Benedetto 2025).

8.2 |. Cardiovascular and Vascular Impact

The systemic oxidant burden initiated by smoke-induced pulmonary autophagy failure has direct consequences for cardiovascular health. Circulating ROS and inflammatory cytokines can impair vascular endothelial autophagy, leading to mitochondrial dysfunction in the vessel walls and accelerating atherosclerotic progression (Cha et al. 2023). Recent evidence also suggests that e-cig use induces circadian protein disruption and oxidative stress (elevated MDA and IFN-γ), mimicking patterns observed in cardiovascular disease (Alzubi et al. 2026).

8.3 |. The Lung-Gut and Lung-Kidney Axis

Interorgan communication is further exemplified by the lunggut axis, where CS exposure increases systemic mediators like C-reactive protein (CRP) and alters intestinal histomorphology and immune networks (Wang et al. 2022). This bidirectional communication suggests that lung epithelial damage can trigger pro-inflammatory responses in colorectal cells via the release of cytokines and Damage-Associated Molecular Patterns (DAMPs) (Rae et al. 2025). Similarly, redox imbalance acts as a mechanistic interface linking pulmonary insults to renal and metabolic vulnerability, predisposing individuals to cardiovascular-kidney-metabolic syndrome (CKMS) (Hsu and Tain 2025).

8.4 |. The Placenta as a Critical Interorgan Interface

Perhaps the most definitive evidence of interorgan communication is found in the maternal–fetal context. Maternal smoking and nicotine exposure disrupt the placental autophagic rheostat, altering its nutrient and oxygen-sensing capabilities through a redox-sensitive nexus (Hsu and Tain 2025). This placental dysfunction directly dictates the developmental trajectory of the fetal lung, programming a lifelong vulnerability to respiratory and inflammatory diseases through a systemic, transgenerational link.

9 |. Maternal Smoking, Fetal Autophagy Disruption, and Developmental Programming of Lung Disease

Maternal smoking imposes a substantial oxidative burden on both the placenta and the developing fetal lung, shifting autophagy from its normal homeostatic function toward maladaptation. Cigarette-smoke–derived ROS overwhelm maternal-fetal antioxidant defenses, leading to excessive AMPK activation and mTOR suppression and thereby distorting the autophagic “redox rheostat” away from its protective range. This redox-driven alteration in autophagic tone disrupts placental nutrient and oxygen sensing, impairs mitochondrial quality control, and interferes with epithelial and mesenchymal differentiation, which are essential for normal lung development (Figure 4).

FIGURE 4 |.

Maternal cigarette smoke, e-cigarette, and nicotine exposure disrupt placental autophagy and program fetal lung dysfunction. The disruption of the maternal–placental–fetal axis is a primary example of interorgan communication, in which dysregulated placental autophagy mediates the systemic programming of fetal organ development and postnatal disease risk. Maternal exposure to cigarette smoke (CS), e-cigarette (EC) aerosols, or nicotine increases oxidative stress and disrupts placental autophagy through alterations in AMPK–mTOR signaling and reduced HDAC activity. Dysregulation of key autophagy mediators, including Beclin-1, LC3, p62, and Parkin, contributes to impaired mitophagy and altered cellular homeostasis. These changes influence fetal lung development, leading to disrupted branching morphogenesis, impaired alveolarization and vascularization, altered immune programming, and inflammatory priming. Collectively, these developmental alterations increase the risk of long-term respiratory consequences, including childhood asthma, reduced lung function, and susceptibility to adult COPD.

Across human and experimental models, maternal smoking and nicotine exposure consistently dysregulate key components of the autophagy-mitophagy machinery, including Beclin-1, LC3, Parkin, p62, and autophagy-related miRNAs, in both the placenta and the fetal lung (McEvoy and Spindel 2017; Thacher et al. 2018; Hollams et al. 2014; Künstle et al. 2024a). These molecular disturbances translate into structural and functional abnormalities, including defective branching morphogenesis, impaired alveolarization and vascularization, altered immune programming, and heightened inflammatory priming. Together, these perturbations establish a persistent developmental “set point” that markedly increases susceptibility to childhood asthma, reduces lung function trajectories, and increases the risk of adult COPD (McEvoy and Spindel 2017; Thacher et al. 2018; Hollams et al. 2014; Künstle et al. 2024a; Gannon et al. 2013). Importantly, similar mechanisms appear to operate with maternal EC exposure. Recent work demonstrates that prenatal exposure to EC aerosol induces aberrant ATG5-dependent autophagy, leading to pulmonary hypertension and inflammatory phenotypes in offspring (Chen et al. 2025). These findings reinforce that both combustible and electronic nicotine delivery systems disrupt autophagy-regulated developmental pathways, programming long-lasting vulnerability to airway disease.

10. |. Autophagy-Mediated Maternal Programming of Lung Immunity

Recent evidence shows that maternal smoke exposure alters immune maturation in offspring through disrupting autophagy. Autophagy is required for the differentiation, metabolic maturation, and tissue residency of lung immune cells, including alveolar macrophages, dendritic cells, and other CD11c + antigen-presenting cells (McEvoy and Spindel 2017). Oxidative stress during the development of immune progenitors can impair maternal–fetal autophagy signaling, disrupting mitochondrial quality control and metabolic programming. These early perturbations alter postnatal inflammatory responses and antigen-presenting capacities (Armstrong et al. 2016; Deretic et al. 2013). Early-life disruptions in autophagy are increasingly linked to immune imbalance, including enhanced type-2 inflammatory responses, impaired immune tolerance, and elevated cytokine production. This review provides a mechanistic explanation for the relation between maternal smoking and a higher risk of asthma and chronic inflammatory lung disease in offspring (Thacher et al. 2018).

In summary, autophagy is multifaceted in the lung: indispensable for development and basal homeostasis; protective by limiting oxidative and inflammatory damage; and potentially pathogenic when dysregulated under chronic stressors such as cigarette smoke, hypoxia, and aging. This bidirectional role helps explain disease heterogeneity and supports targeting autophagy quality and flux, rather than simple “on/off” modulation, in future interventions. Because these adaptive/maladaptive shifts require sustained transcriptional reprogramming, epigenetic mechanisms (HDAC/HAT balance, AMPK–mTOR–chromatin crosstalk, and ncRNAs) are key determinants of autophagy tone in the smoke-exposed lung.

11 |. Epigenetics Gates the Autophagy Program

Broadly, autophagy is not only a post-translational pathway but also transcriptionally regulated by epigenetic mechanisms via histone deacetylase/acetyltransferase (HDAC/HAT) and DNA methylation/demethylation (Hu 2019). Non-coding RNAs (miRNAs and other ncRNAs) provide additional epigenetic control by regulating autophagy, both directly (by targeting ATG/BECN1/ TFEB pathway transcripts) and indirectly by modulating the expression of epigenetic enzymes (HDACs, HATs, DNMTs). In stress (e.g., nutrient limitation), cells reconfigure chromatin to shut down genes that regulate dispensable pathways and turn on survival pathways, such as autophagy. This is achieved through histone modifications and other epigenetic marks that open the promoters/enhancers of autophagy genes (e.g., ATGs, BECN1, TFEB network), thereby increasing autophagic flux (Yu et al. 2023).

Similarly, CS-triggered responses are tightly shaped by epigenetic control, notably histone modifications and chromatin remodeling, and by upstream metabolic sensors (AMPK/mTOR) that interface with epigenetic enzymes. Specifically, CS induces oxidative and carbonyl stress, which alters epigenetic regulators. A key and reproducible change is the downregulation/inhibition of HDACs in airway/lung tissue. In vitro, CS extract-induced activation of autophagy is linked to decreased HDAC activity, consistent with the model that loss of HDAC function leads to hyperacetylated chromatin and heightened transcription of autophagy genes (Ryter et al. 2010). Clinically, severe COPD lungs also show reduced HDAC activity, consistent with persistent, maladaptive stress responses (including autophagy) that, as outlined above, contribute to epithelial injury, impaired proteostasis, and aberrant inflammation (Hu 2019).

12 |. Energy Sensors Connect Epigenetics to Autophagy

AMPK functions as the metabolic “on” switch for autophagy. Under smoke- or stress-induced ATP depletion and ROS generation, AMPK, in addition to activating ULK1, directly remodels chromatin by phosphorylating histones, DNMTs, and histone-modifying enzymes, thereby creating an epigenetic landscape for autophagy gene transcription (Yu et al. 2023). In contrast, when nutrients are plentiful, mTORC1 promotes acetyltransferase activity that acetylates core autophagy proteins and autophagy/lysosome transcriptional targets, repressing autophagy while supporting translation and growth. Under stress, including nutrient/energy stress triggered by CS, mTORC1 is suppressed, thereby releasing the acetylation-mediated brake and favoring autophagy (Shi et al. 2021). Taken together, AMPK activation and/or mTORC1 inhibition translate CS-related energetic and oxidative stress into epigenetically regulated autophagy, helping initiate a protective program that can become maladaptive with chronic exposure.

13 |. Therapeutic Targets and Biomarker Opportunities in Autophagy Dysregulation

Several studies have demonstrated that autophagy plays a critical role in asthma progression, particularly in terms of fibroblast survival and airway remodeling (Qian et al. 2025). Autophagy dysfunction leads to abnormal apoptosis in fibroblasts, thereby promoting their persistence and enhanced production of pro-fibrotic mediators such as TGF-β (Ramakrishnan et al. 2020; McAlinden et al. 2019). This cascade promotes the accumulation of extracellular matrix and structural changes to airways that characterize severe, treatment-refractory asthma (Ghavami et al. 2015). Hence, therapeutic approaches aimed at improving autophagic homeostasis may offer an alternative strategy to limit fibroblast-driven remodeling. By integrating autophagy-targeting agents with existing anti-inflammatory and biologic therapies, it may be possible to more effectively disrupt the remodeling process and reduce disease (Liu et al. 2025; Wang et al. 2025).

14 |. Translational Outlook

Understanding autophagy as a redox- and epigenetically regulated rheostat rather than a simple on/off pathway has significant translational implications. Targeting autophagic flux, particularly restoring lysosomal function and TFEB-driven lysosomal biogenesis, may offer more effective therapeutic strategies than global autophagy induction. Activation of TFEB enhances lysosomal degradative capacity and improves autophagic clearance, while CS and vaping aerosols impair TFEB nuclear translocation and lysosomal acidity (Pehote et al. 2017; Bodas et al. 2017). Early studies also show that correcting HDAC deficits or enhancing mitochondrial quality control can mitigate nicotine-, smoke-, or vaping-induced epithelial injury (Ryter et al. 2010).

Autophagy-related structural changes, such as aggresome burden, may serve as biomarkers of disease severity and therapeutic response, as they correlate with emphysema progression in COPD (Vij et al. 2018). Together, these findings point toward precision modulation of autophagy, i.e., restoring flux, lysosomal competence, and epigenetic balance, as a promising avenue for future therapies targeting smoking-, vaping-, and nicotine-related lung disease.

Additional therapeutic opportunities arise from targeting upstream modifiers of redox and epigenetic stress. Antioxidant strategies, including mitochondrial-targeted ROS scavengers, have been shown to partially restore autophagic balance in CS- and nicotine-exposed cells (Hur et al. 2022). Epigenetic modulators, such as HDAC-activating compounds, may reverse smoke-induced reductions in HDAC activity, thereby correcting aberrant autophagy gene expression (Ryter et al. 2010). Agents that specifically enhance autophagy flux, such as rapalogs, mitophagy stabilizers, and TFEB activators, represent promising candidates for restoring lysosomal competence in chronic smoke or EC exposure. Beyond aggresomes, emerging autophagy-related biomarkers, including ATG transcript signatures and autophagy-regulating miRNAs, may help stratify risk and personalize future interventions.

15 |. Future Directions

Future research should prioritize cell-type-specific mapping of autophagic flux using single-cell and multi-omic platforms to distinguish adaptive from maladaptive autophagy in epithelial, fibroblast, endothelial, and immune populations (Khalafiyan et al. 2024). Beyond mitophagy, other selective autophagy pathways, such as ER-phagy, xenophagy, and lipophagy, require deeper investigation, as they are increasingly recognized as contributors to CS-, e-cig-, and nicotine-induced lung injury (Ryter and Choi 2015; Nakahira and Choi 2013). In maternal-fetal contexts, more longitudinal studies are needed to determine how early autophagy dysregulation programs lifelong respiratory vulnerability (Thacher et al. 2018; Künstle et al. 2024a). Finally, the emerging intersection of autophagy and epigenetic memory raises new questions about how smoke-, EC vapor-, or nicotine-induced chromatin alterations persist over time and influence autophagic tone (Hu 2019). Collectively, these future directions highlight opportunities to develop targeted autophagy-modulating interventions and to identify biomarkers that capture early injury and long-term risk.

16 |. Conclusion

In this review, we propose that autophagy functions as a redox-sensitive rheostat that integrates cellular responses to cigarette smoke, electronic cigarettes, nicotine, and developmental exposures. Under physiological conditions, autophagy preserves proteostasis, mitochondrial quality control, and immune homeostasis; however, chronic or excessive exposure shifts this pathway toward maladaptive flux impairment, lysosomal dysfunction, inflammatory signaling, and tissue remodeling. These alterations contribute not only to chronic lung diseases such as asthma and COPD but also to systemic consequences mediated by interorgan communication, including effects on the cardiovascular system, the lung-gut and lung-kidney axes, and the maternal-placental-fetal interface. Framing autophagy as a dynamic regulator of redox balance, immune programming, and multi-organ stress responses provides a unifying mechanistic model for smoke- and nicotine-related disease. This perspective also highlights the need for future biomarker development and therapeutic strategies aimed at restoring the quality, completion, and lysosomal competence of autophagy, rather than simply nonspecifically increasing autophagy.

Data Availability Statement

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