Chronic lung diseases linked to long-term inhalation exposure are a major challenge in occupational and environmental health. Continuous contact with particulate matter and occupational dust, including crystalline silica, coal dust and diesel exhaust particles, can sustain oxidative and inflammatory stress in the airways and lung parenchyma, contributing to epithelial injury, immune dysregulation and progressive structural remodeling (1-4). A key mechanism in this process is oxidative stress, defined as an imbalance between oxidant generation and antioxidant defenses that interferes with redox signaling and promotes molecular damage (5). Reactive oxygen species (ROS) and reactive nitrogen species are not only by-products of exposure-associated injury but also key signaling mediators: While physiological levels are required for normal cell function, their excess may drive chronic inflammation and tissue damage (6).

Given the key role of redox imbalance in inflammatory lung diseases, antioxidant-based strategies are considered a potential approach for prevention and disease modification (7). Early research has primarily focused on classical antioxidant vitamins, such as vitamins C and E, based on their ability to scavenge ROS in experimental systems (8,9). However, accumulating clinical evidence has demonstrated limited or inconsistent benefits of vitamin supplementation in chronic diseases characterized by persistent oxidative injury, and in certain contexts has suggested adverse effects (10) such as increased mortality associated with β-carotene and vitamin E supplementation (11). These findings indicate that direct neutralization of reactive species may be insufficient to counteract complex redox disturbances associated with chronic inhalation exposure, where oxidative processes are sustained, compartmentalized and associated with inflammatory and immune signaling pathways in the lung, including NF-κB-dependent inflammatory activation (12-14). The proposed mechanistic framework linking inhalation-induced oxidative stress and chronic lung injury, along with potential modulatory effects of polyphenols, is illustrated in Fig. 1. Nevertheless, the effects of polyphenols are complex and context-dependent. Among naturally occurring antioxidants, polyphenols have received attention because, in addition to their antioxidant properties, they modulate redox-sensitive signaling pathways involved in oxidative stress and inflammation (15,16). Antioxidant activity observed in cell-free or in vitro systems does not necessarily translate into direct radical scavenging effects in vivo, where bioavailability, metabolism and tissue distribution are variable (17,18). In the respiratory system, polyphenols may therefore act predominantly through indirect mechanisms, including modulation of key redox-sensitive pathways, particularly nuclear factor erythroid 2-related factor 2 (Nrf2)/Keap1 axis and NF-κB signaling, which are critically involved in oxidative stress responses, inflammation and epithelial homeostasis in chronic inhalation-associated lung diseases (19,20). Experimental studies have suggested that specific polyphenols, such as quercetin, epigallocatechin gallate and resveratrol, can attenuate oxidative and inflammatory responses in pulmonary cells, although the extent to which these effects translate into clinical benefit remains uncertain (21-23). Interindividual variability in the metabolism and biological effects of polyphenols may be influenced by differences in gut microbiota composition, since intestinal microorganisms generate metabolites the activity of which may vary across individuals (24). Given their biological importance, it is useful to consider the major dietary sources of polyphenols. Polyphenols are widely distributed in plant-derived foods, including fruits such as apples, blueberries, chokeberries and rose-hips, and vegetables such as broccoli and onions, as well as olives (21,25). Epidemiological studies have also suggested that higher consumption of polyphenol-rich foods is associated with a decreased risk of cancer and cardiovascular diseases (26,27).

The biological effects of dietary polyphenols are determined by their bioavailability rather than solely by their concentration in foods (28,29). Bioavailability is influenced by multiple factors, including release from the food matrix (the physical and chemical environment of the food) during digestion, chemical stability, intestinal absorption and microbial biotransformation in the gut. As a result, a high polyphenol content does not necessarily translate into strong in vivo activity. An additional limitation relates to the generally low bioavailability of numerous dietary polyphenols. Following ingestion, these compounds undergo extensive metabolism in the intestine and liver, resulting primarily in conjugated and microbiota-derived metabolites rather than the parent compounds typically tested in experimental studies. This discrepancy between the bioactivity of parent polyphenols and circulating metabolites represents an important consideration when interpreting experimental findings. A potential solution to this problem is microencapsulation and microemulsions (30).

Evidence from experimental and clinical studies has suggested the potential relevance of polyphenols in respiratory conditions (23,31,32); however, to the best of our knowledge, their role in chronic lung diseases related to inhalation-induced oxidative stress has not been comprehensively evaluated. Existing studies vary regarding exposure types, disease phenotypes [including pneumoconiosis, chronic bronchitis and chronic obstructive pulmonary disease (COPD)], polyphenol source and assessed outcomes, making it difficult to draw coherent conclusions about their preventive or supportive value in respiratory pathology. Current literature predominantly addresses cardiovascular, metabolic and neurodegenerative outcomes, leaving a gap in the systematic evaluation of occupational and environmentally induced chronic lung disease (33). A systematic synthesis of the available data is therefore required to clarify the relevance of polyphenols in modulating oxidative stress-driven mechanisms in chronic lung disease associated with inhalation exposure.

The present review aimed to integrate available experimental and clinical evidence on the role of plant-derived polyphenols in chronic lung diseases associated with inhalation-induced oxidative stress, focusing on the underlying mechanisms, preventive potential and implications for disease management and rehabilitation.

The present systematic review integrates experimental and clinical evidence on the role of plant-derived polyphenols in chronic lung disease associated with inhalation-induced oxidative stress. Preclinical studies consistently demonstrated attenuation of oxidative stress, suppression of inflammatory signaling and partial preservation of lung structure following polyphenol exposure (40,42,45,47,52,56). By contrast, clinical findings were more heterogeneous, with relatively consistent improvements in biochemical and inflammatory markers but variable effects on spirometric outcomes. These findings suggested that polyphenols reliably modulate redox-sensitive and inflammatory pathways under controlled experimental conditions, whereas translation into measurable functional improvement in humans remains uncertain (12,57). This may reflect the complex and long-standing nature of structural lung damage, which may not be easily reversible even when oxidative and inflammatory pathways are modulated (58).

Notably, oxidative stress and inflammatory markers appeared more responsive to polyphenol intervention than established functional endpoints. This suggests that polyphenols may preferentially influence upstream molecular and inflammatory processes, potentially affecting disease trajectory rather than acutely reversing airflow limitation (59,60). No consistent safety concerns were identified, supporting further investigation of polyphenols as adjunctive strategies in chronic inhalation-associated lung disease.

The consistency of findings across preclinical models supports the hypothesis that polyphenols primarily act via modulation of redox-sensitive signaling pathways (61). In certain in vivo and in vitro systems, activation of Nrf2-associated antioxidant responses and attenuation of NF-κB-mediated inflammatory signaling were recurrent mechanistic themes (62,63). This aligns with the hypothesis that chronic inhalation-induced lung injury is driven not only by excess ROS, but also by dysregulated redox signaling networks that amplify inflammatory and remodeling cascades (58,64). Although Nrf2 activation and NF-κB inhibition were recurrent mechanistic themes, comparison of the included studies indicates that different polyphenols do not act through a single conserved signaling pathway. Distinct compounds were associated with modulation of different molecular targets. Several polyphenols, including gallic acid, magnolol and luteolin, were more frequently associated with Nrf2-associated antioxidant signaling, whereas curcumin predominantly modulated inflammatory pathways. Curcumin attenuates inflammation and oxidative stress through modulation of the PTEN/PI3K/AKT/NF-κB signaling pathway (65). By contrast, resveratrol and the stilbene derivative gaylussacin were more consistently associated with sirtuin 1 (SIRT1)-associated signaling, while quercetin demonstrated SIRT1-dependent regulation of MMP expression. However, because structurally related compounds were not systematically compared under standardized experimental conditions, definitive structure-activity associations cannot yet be established. These observations may explain why classical antioxidant supplementation has yielded limited clinical benefit. Direct neutralization of reactive species is unlikely to sufficiently address sustained, compartmentalized oxidative stress or downstream transcriptional activation. By contrast, polyphenols may influence endogenous antioxidant defenses and inflammatory pathways more broadly, supporting a more integrated regulation of redox balance.

However, the translational gap between mechanistic efficacy and clinical impact remains evident (31). While experimental models capture early oxidative and inflammatory processes, clinical populations typically represent advanced disease stages characterized by established structural remodeling, airway narrowing and irreversible parenchymal damage (66). Under such conditions, modulation of oxidative pathways alone may not translate into substantial improvements in spirometric indices, even if biochemical and symptomatic benefits are observed (67,68). The mechanistic evidence supports biological plausibility for polyphenols as modulators of inhalation-induced redox imbalance, but also underscores the need to consider disease stage, timing of intervention and combination strategies in future clinical investigations.

The effects of polyphenols differed according to disease context and exposure model. In COPD and cigarette smoke-associated models, preclinical studies consistently demonstrated attenuation of oxidative stress and inflammation (40,42,45), whereas clinical trials show more variable effects, particularly on spirometric outcomes (32,53). This may reflect the limited reversibility of established structural damage despite modulation of upstream redox and inflammatory pathways (69). In chemically or toxicant-induced lung injury models, polyphenols exerted more pronounced effects on inflammatory and fibrotic parameters, potentially due to the more defined oxidative drivers of injury in these systems (39,56,70). However, clinical evidence in toxic inhalation-associated disease remains limited, and functional respiratory outcomes are not consistently improved. Overall, disease stage, exposure characteristics and endpoint selection may influence the observable impact of polyphenol interventions.

The present review integrates clinical and preclinical evidence within a unified mechanistic framework, enabling translational interpretation across biological levels. Risk of bias was assessed using validated tools appropriate to each study design and findings were synthesized descriptively in line with established methodological standards. However, clinical evidence base remains limited, with most randomized trials including small sample sizes and relatively short intervention durations. These factors decrease the likelihood of detecting changes in structural or functional respiratory endpoints. The findings should be interpreted in the context of the risk of bias assessment. Although none of the included randomized clinical trials were judged to be at high risk of bias, most were assessed as having some concerns, decreasing confidence in the reported clinical benefits. Similarly, the predominance of unclear risk of bias among the preclinical studies, primarily reflecting incomplete methodological reporting, warrants cautious interpretation of the mechanistic findings. Several factors contributed to the substantial heterogeneity across the included studies. First, different polyphenols and polyphenol classes were investigated, ranging from flavonoids and stilbenes to curcuminoids and polyphenol-rich extracts. Second, considerable variation existed in formulations, dosing regimens and intervention duration. Third, the included evidence comprised in vitro studies, animal models and clinical trials, each providing complementary but different types of evidence. Finally, studies differed in disease phenotypes, exposure model and outcome measures. These methodological differences limit direct comparisons between studies, preclude quantitative meta-analysis, and should be considered when interpreting the consistency and clinical applicability of the available evidence.

Extrapolation from animal and in vitro models to human disease must be approached cautiously due to differences in exposure duration, metabolism and disease chronicity (37,71). In addition, most studies evaluated polyphenols as adjunctive interventions and long-term clinical outcomes such as disease progression or exacerbation frequency were rarely assessed (38,44,48). Consequently, conclusions regarding sustained disease modification remain preliminary. Overall, confidence in the preclinical oxidative and inflammatory findings was greater than confidence in the clinical functional evidence, which was limited by heterogeneity, small trial sizes and methodological concerns.

The present review suggested that polyphenols may represent a biologically plausible adjunctive strategy in chronic lung diseases characterized by inhalation-induced oxidative stress (72). While consistent modulation of oxidative and inflammatory markers has been demonstrated across experimental systems, clinical benefits are modest and may depend on disease stage, intervention timing and endpoint selection. Polyphenols are therefore unlikely to reverse established structural lung damage but may contribute to modulation of ongoing redox and inflammatory activity within a multimodal therapeutic framework. However, a biologically plausible mechanism does not establish therapeutic value, particularly when the available clinical evidence remains limited. The clinical trials underlying this evidence base are few, generally small, of short duration and have reported inconsistent functional outcomes. Accordingly, the present data are not sufficient to support the broad clinical use of polyphenols in chronic lung diseases associated with inhalation-induced oxidative stress. Nonetheless, given the growing global burden of occupational and environmental lung disease (73,74), strategies targeting redox-sensitive pathways may hold relevance in high-exposure populations where preventive or adjunctive approaches are needed (75).

Future clinical research should prioritize adequately powered randomized trials with longer intervention durations and clearly defined patient populations. Improved standardization of polyphenol formulations, dosing regimens, intervention duration and outcome assessment is key, as variability in these methodological aspects remains a major limitation for translating experimental findings into clinical practice. Consistent intervention protocols, outcome measures and reporting standards will also be critical to reduce heterogeneity and improve comparability across studies. Greater emphasis on clinically meaningful endpoints such as exacerbation frequency, symptom burden and disease progression may clarify whether redox modulation translates into sustained functional benefit. Mechanistic studies that better integrate pharmacokinetics, bioavailability and tissue distribution in chronic exposure settings are also warranted. Bridging experimental and clinical research through well-designed translational studies may determine whether targeting redox sensitive pathways can meaningfully alter the trajectory of inhalation-associated lung disease.

In conclusion, plant-derived polyphenols are biologically plausible modulators of inhalation-induced oxidative stress. However, their clinical benefit remains unproven. Given the limited number, small size and heterogeneity of the available clinical trials, current evidence does not support recommending a specific polyphenol, formulation or dosage for routine clinical use in chronic lung disease. Future adequately powered randomized controlled trials using standardized, bioavailability-optimized formulations are needed to determine optimal dosing strategies and clarify the efficacy of individual polyphenols in specific chronic lung diseases.