ALI/ARDS has consistently been a primary cause of acute respiratory exhaustion in seriously ill patients, with high incidence and mortality rates over the past 20 years (Fielding-Singh et al., 2018). According to the “International Sepsis Consensus 5.0 Guidelines” (fifth edition, 2021) (Evans et al., 2021), sepsis is a multi-organ dysfunction caused by a dysregulated host inflammatory response to infection (Cavaillon and Chrétien, 2019; Cecconi et al., 2018). The lungs are the most affected and vulnerable target organs in the process of multiple organ dysfunction caused by sepsis (Fan and Fan, 2018). The pathophysiological process of sepsis-associated acute lung injury (SALI) involves disruption in epithelial and endothelial cell function, excessive accumulation and activation of immune cells, inflammatory response, oxidative stress, programmed cell death, and mobilization of coagulation pathways (Sun et al., 2023). Given the relatively high mortality rate and medical burden, ARDS interventions have always been at the forefront of critical care. Because current treatments for ALI are limited and face additional challenges, the introduction of alternative or complementary treatment methods is necessary (Patel et al., 2018). Fortunately, several “conventional” pharmacological therapies for ALI have been found to reduce mortality. Considering that luteolin is expected to have good effects on ALI, numerous studies have utilized luteolin to explore various cell and animal models induced by Lipopolysaccharide (LPS), demonstrating that luteolin exerts its effects on LPS-induced ALI by acting on multiple pathways involved in the pathogenesis of LPS-induced ALI (Figure 4).

Respiratory viruses are a substantial threat to human wellbeing, and respiratory syncytial virus (RSV) is the primary cause of respiratory infections. Studies by Weifeng Li et al. have shown that luteolin exerts therapeutic effects on RSV pneumonia through various mechanisms. Luteolin mitigates lung inflammation in mice, curbs RSV proliferation in the lungs, elevates pulmonary IFN-β and interferon-stimulated genes (ISG) expression, and modulates murine glucose metabolism. AMs constitute the chief producers of IFN-β in the lungs at the beginning of RSV infection, and the absence of AMs can exacerbate RSV-induced lung tissue damage. Luteolin predominantly targets AMs. By safeguarding the mitochondria in AMs and curbing oxidative stress within cells, luteolin can prevent RSV-induced apoptosis and stimulate IFN-β secretion by AMs (Li W. et al., 2024). Luteolin exerts anti-inflammatory effects on lung tissue in rat models of acute pneumonia. Results from the study by Kong et al. indicated that luteolin inhibits inflammation by suppressing cAMP-phosphodiesterase (cAMP-PDE) activity and the expression of microvascular endothelial cell adhesion molecules (Kong et al., 2019). S. aureus infections can range from mild skin infections to acute diseases such as pneumonia (David and Daum, 2010). Yuan et al. showed that the expression of genes involved in virulence and biofilm formation in S. aureus strains was downregulated after treatment with luteolin, confirming the potential anti-virulence effects of luteolin (Yuan et al., 2022). Additionally, Yuan et al. found that luteolin treatment mitigated the damage to human alveolar epithelial A549 cells caused by the wild-type (WT) strain and protected mice from pneumonia induced by the WT strain. They suggested that luteolin is a promising metabolite that can interfere with the agr system and can be developed as a novel therapeutic agent for S. aureus infections (Lv et al., 2023). Moreover, docking studies with methicillin-resistant Staphylococcus aureus (MRSA) strains showed that luteolin exhibits good pharmacokinetics, drug-likeness, and high binding energy with MRSA strains. Ligands with good binding energy values, pharmacokinetics, and drug-likeness have been proven to be potential ligands for treating MRSA infections, and luteolin may serve as a potential therapeutic inhibitor of pneumonia caused by MRSA (Nandhini et al., 2023). At the end of 2019, an outbreak of novel acute viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a severe medical and economic crisis. SARS-CoV-2 uses the receptor-binding domain (RBD) of its spike protein to bind to angiotensin-converting enzyme 2 (ACE2) in host cells (Zhu et al., 2023). Therefore, metabolites that bind to human ACE2 or the SARS-CoV-2 spike protein may block the SARS-CoV-2-ACE2 receptor interaction (Day et al., 2021). Luteolin has been shown to bind and significantly inhibit SARS-CoV infection (Stalin et al., 2022). Stalin et al. used computational simulations and virtual screening methods to demonstrate that luteolin engages in uniquely strong interactions with hotspots in the RBD of the SARS-CoV-2 RBD/ACE2 complex, inhibiting the infection of SARS-CoV-2 (Figure 5) (Stalin et al., 2022). In summary, luteolin and its derivatives demonstrate therapeutic potential through multiple mechanisms, such as inhibiting cAMP-PDE activity and the expression of adhesion molecules on microvascular endothelial cells, enhancing pulmonary IFN-β and ISG expression while regulating glucose metabolism in mice, protecting AMs mitochondria and suppressing intracellular oxidative stress to prevent RSV-induced cell apoptosis and stimulate AMs secretion of IFN-β, enhancing the blockade of the RBD/ACE2 complex to inhibit SARS-CoV-2 infection, and downregulating gene expression in S. aureus strains. These actions collectively contribute to anti-inflammatory effects, protection of AMs, inhibition of pathogen proliferation, metabolic regulation, and direct interference with virus-host cell receptor interactions, showing promise in treating respiratory diseases. This not only provides a scientific basis for the development of luteolin as a new type of anti-pneumonia drug but also deepens our understanding of the potential of plant-derived metabolites in modern medicine. We look forward to future clinical trials that can further verify these findings and explore new uses for luteolin in treating pneumonia.

Asthma is a common chronic airway disease characterized by airway narrowing, thickening of the airway walls, and increased airway mucus secretion, which leads to restricted airflow. The clinical features include dyspnea, wheezing, chest tightness, and cough. The prevalence and incidence of asthma has increased significantly. Asthma affected approximately 262 million people in 2019 and was responsible for 455,000 deaths that year. The asthma mortality rate is highest in low and middle sociodemographic index (SDI) countries, whereas its prevalence is highest in high-SDI countries (GBD 2019 Diseases and Injuries Collaborators, 2020). During the sensitization process and after sensitization in a model of ovalbumin (OVA)-sensitized airway hyperresponsive male BALB/c mice aged 8–9 weeks, the administration of luteolin (0.1 mg/kg body weight led to a marked reduction in OVA-induced constriction of the airways and bronchial hyperreactivity, in contrast to the control group. Luteolin also reduced the levels of OVA-specific IgE in the serum, increased the levels of interferon-gamma (IFN-γ), and decreased the levels of interleukin-4 (IL-4) and interleukin-5 (IL-5) in the BALF, attenuating the asthmatic characteristics of the experimental mice (Das et al., 2003). Luteolin alleviates bronchoconstriction and airway hyperresponsiveness in OVA-sensitized mice. Luteolin exerts anti-asthmatic activity against OVA-induced pulmonary inflammation by downregulating the transcription of CD4⁺ T cells with Th2 phenotype cytokines and inhibiting the production of Prostaglandin E2 (PGE2) (Jin et al., 2009). Luteolin attenuates the immediate and late asthmatic responses to nebulized OVA exposure in conscious guinea pigs. Compared to the control group, luteolin, and apigenin significantly reduced specific airway resistance in both immediate and late asthmatic responses. They also reduced the recruitment of leukocytes and release of histamines, as well as the activity of phospholipase A2 (PLA2) and eosinophil peroxidase (EPO) in bronchoalveolar lavage fluid (BALF). Still, the anti-asthmatic activity of luteolin was lower than that of sodium cromoglycate and dexamethasone (Lee et al., 2014). Therefore, luteolin can be used not only as a lead molecule for identifying effective anti-asthmatic therapies but also as a means of identifying novel anti-asthmatic targets (Figure 6). In addition, luteolin reduces autophagy in allergic asthma. They observed that luteolin treatment significantly inhibited OVA-induced inflammatory responses and autophagy in the lung tissue. Moreover, luteolin activated the PI3K/Akt/mTOR pathway in the lung tissues of asthmatic mice and inhibited the Beclin-1-PI3KC3 protein complex. This strategy encompasses the prevention of autophagic processes in allergic asthma via upregulation of the PI3K/Akt/mTOR pathway and downregulation of the Beclin-1-PI3KC3 complex (Wang S. et al., 2021). Asthma often manifests as an excessive buildup of mucus in the airway lining, which can lead to severe clinical outcomes. Although general asthma therapies are effective, specialized treatments designed to limit mucus overproduction in patients with asthma are still lacking. Recent studies have revealed that stimulating the gamma-aminobutyric acid type A receptor (GABAAR) is crucial for promoting excessive mucus secretion by pulmonary airway epithelial cells. Shen and colleagues found that in an OVA-induced asthma mouse model, with a 10 mg/kg administration, luteolin markedly reduced the number of goblet cells within pulmonary tissue and suppressed excessive mucus production. Luteolin hindered GABAAR-induced currents in A549 cells, according to patch-clamp data. Additionally, the suppressive effects of luteolin on goblet cell hyperplasia and excessive mucus secretion induced by OVA are reversed by picrotoxin, a GABAAR antagonist (Shen et al., 2016). In summary, luteolin and its derivatives have demonstrated potential in treating asthma by modulating various cellular signaling pathways and immune responses. These include the activation of the PI3K/Akt/mTOR pathway and inhibition of the Beclin-1-PI3KC3 protein complex. The therapeutic potential is reflected in mechanisms such as reducing airway inflammation, decreasing airway hyperresponsiveness, modulating immune cytokines, reducing eosinophil infiltration, inhibiting autophagy, and suppressing excessive mucus secretion. After evaluating the potential impact of luteolin on asthma, we believe that this metabolite shows promise for improving asthma symptoms by modulating various cellular signaling pathways and immune responses. Nonetheless, we should recognize the complexity of asthma, which necessitates further research to determine the optimal dose of luteolin for asthma treatment. We are confident that with a deeper understanding of the mechanisms of action of luteolin, it could become an important metabolite in future asthma treatment strategies.

COPD is one of the leading causes of morbidity and mortality worldwide (Buhl et al., 2024) and poses a significant economic and social burden (Alupo et al., 2024). Patients experience progressive deterioration until end-stage COPD, which is characterized by severe airflow limitations, severely compromised lung function, chronic respiratory failure, advanced age, multiple comorbidities, and severe systemic manifestations/complications. COPD is often underdiagnosed and undertreated (Viegi et al., 2007). Intensified oxidative stress and body-wide inflammation are critical elements of the complex pathophysiology of COPD (Austin et al., 2016). Studies have shown that matrix metalloproteinases (MMPs) are associated with COPD progression, and luteolin has been identified as an inhibitor of MMP-2 and MMP-9 (Ende and Gebhardt, 2004). Therefore, Yaghi et al. explored the use of luteolin in their study, measuring ciliary beat frequency (CBF) in nasal cilia from COPD patients as an important indicator of ciliary function in COPD. Compared to the high-risk and control groups, CBF was significantly reduced in individuals with moderate-to-severe COPD. The treatment group observed a significant and sustained increase in CBF in COPD cilia tested with luteolin, increasing the CBF of cilia in patients with COPD, favorably enhancing mucociliary clearance, reducing retention of secretions, and decreasing infections (Yaghi et al., 2012). Li et al. proposed that luteolin inhibits inflammation and oxidative stress in COPD by suppressing the NADPH oxidase 4 (NOX4)-mediated NF-κB signaling pathway. Studies have used cigarette smoke (CS) to induce COPD in mice or A549 cells both in vivo and in vitro. In vivo, luteolin mitigated the inhibitory effects of CS on body weight and the activities of SOD and CAT in COPD model mice and reduced the levels of MDA. Similar results have been obtained in vitro. Li et al. transfected A549 cells with a NOX4 overexpression plasmid to induce NOX4 overexpression. Compared to the control group, the overexpression of NOX4 reversed the downregulation of the ratio of p-p65/p65 and p-IκB/IκB in the luteolin group, upregulation of oxidative stress-related proteins, and reduction of inflammatory-related factors. Luteolin alleviates inflammation, oxidative stress, and activation of the NOX4-mediated NF-κB signaling pathway induced by CS in A549 cells (Li M. et al., 2023). Zhou and colleagues proposed that luteolin alleviates oxidative stress induced by CS in COPD by modulating the transient receptor potential vanilloid type 1 (TRPV1) and cytochrome P450 family 2 subfamily A member 13 (CYP2A13)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways. They observed that luteolin downregulated the expression of TRPV1 and CYP2A13 proteins and upregulated the expression of sirtuin 6 (SIRT6) and NRF2 proteins in CS + LPS-induced COPD mice and A549 cells treated with CS. CS treatment increased intracellular calcium ions, overall ROS, and mitochondria-derived ROS levels in A549 cells. Importantly, luteolin inhibited the influx of Ca²⁺ into CS-treated A549 cells and mitigated the excessive production of mitochondrial and intracellular ROS. By modulating the TRPV1/SIRT6 and CYP2A13/NRF2 signaling pathways, luteolin exhibits a protective effect by reducing oxidative stress and inflammation in COPD mice induced by CS-and LPS, as well as in A549 cells exposed to CS (Figure 7) (Zhou et al., 2023). In summary, luteolin has the potential to alleviate inflammation and oxidative stress and improve cilia function in COPD by inhibiting NOX4-mediated NF-κB signaling pathway, regulating TRPV1 and CYP2A13/NRF2 signaling pathways, and modulating various signaling pathways and cytokines. However, we are also aware that COPD is a multifactorial disease requiring a comprehensive treatment strategy. Therefore, future research should explore the combined application of luteolin and other drugs to manage COPD effectively.

Idiopathic pulmonary fibrosis (IPF), classified as progressive fibrosing interstitial lung disease (ILD), leads to a gradual decline in lung function (Raghu et al., 2018). The hallmarks of IPF include a progressive deterioration in lung capacity, exacerbation of fibrosis as depicted on high-resolution computed tomography (HRCT) scans, decline in both symptomatology and quality of life for patients, and a propensity for early death (Travis et al., 2013; Wells et al., 2018; Cottin et al., 2019; Kolb and Vašáková, 2019). Aside from pirfenidone and nintedanib, which are specifically used for treating IPF, no other medications have been approved for treating ILDs (Brown et al., 2020). The predominant pharmacological approach for treating other progressive fibrosing ILDs involves immunosuppression (Cottin et al., 2019). When the fibrotic response of an ILD to lung injury advances to a stage where fibrosis becomes self-perpetuating and continues to progress, targeted anti-fibrotic therapy is essential to mitigate the rate of disease progression. Clinical studies have demonstrated that natural substances extracted from plants possess potent antifibrotic properties and can alleviate dyspnea, a common and debilitating symptom experienced by patients with ILD (Chang et al., 2021). Luteolin is an active flavonoid metabolite isolated from Lonicera japonica and is known for its broad range of biological activities, particularly its antioxidant and anti-inflammatory effects. Ren and colleagues loaded luteolin into γ-cyclodextrin metal-organic frameworks (CD-MOFs) for pulmonary drug delivery using a dry powder inhaler. In vitro lung deposition results showed that luteolin effectively inhibited the progression of ILD in bleomycin (BLM)-induced fibrotic ILD rat model. Compared to the control group, treatment with luteolin significantly protected rats from BLM-induced lung injury. They demonstrated that luteolin possesses potent anti-inflammatory activity and that inhalation of luteolin could be considered a promising new strategy for treating fibrotic ILD (Ren et al., 2023). Oral administration of luteolin (10 mg/kg) in both the early and delayed luteolin treatment groups effectively inhibited the infiltration of neutrophils into BALF and increased TNF-R and IL-6 levels in C57BL/6 mice intubated with BLM. Luteolin also mitigated collagen deposition, TGF-β1 expression, and pulmonary fibrosis following BLM injection. Subsequently, in vitro studies showed that luteolin inhibited the expression of TGF-β1-induced reactive serum myoglobin (R-SMA), type I collagen, and vimentin in primary cultured mouse lung fibroblasts. Luteolin significantly blocked the downregulation of epithelial markers (E-cadherin) and upregulation of mesenchymal cell markers (fibronectin and vimentin) mediated by TGF-β1 and maintained the epithelial morphology of human alveolar epithelial-derived A549 cells. This indicates that luteolin exerts effective antifibrotic activity by inhibiting pulmonary inflammation and suppressing myofibroblast differentiation and the epithelial-mesenchymal transition (EMT) of cells (Chen et al., 2010). Data analysis in informatics implied that luteolin may offer substantial therapeutic benefits in treating IPF and gastroesophageal reflux disease (GERD). By identifying and analyzing differentially expressed genes (DEGs) between IPF and GERD and predicting drug molecules for IPF and GERD, luteolin was recognized as a potential biomarker and promising therapeutic target for both IPF and GERD (Table 2) (Shen et al., 2016). In summary, luteolin demonstrates potential in the treatment of IPF through various mechanisms, including anti-inflammatory effects, anti-fibrotic actions (inhibition of Smad3 phosphorylation in the TGF-β1 signaling pathway), inhibition of myofibroblast differentiation, suppression of EMT, modulation of key signaling pathways, and potential as a drug delivery vehicle. After analyzing the potential applications of luteolin in treating pulmonary fibrosis, we were encouraged by the antifibrotic potential of the metabolite. We believe that luteolin’s anti-inflammatory and anti-fibrotic properties and its role in modulating key signaling pathways make it a strong candidate for treating pulmonary fibrosis. Future studies should focus on determining the optimal route of administration and luteolin dosage to maximize its therapeutic effects.

The GLOBOCAN 2020 estimates from the International Agency for Research on Cancer (IARC) regarding cancer incidence and mortality rates show that carcinoma of the lung stands as the most prevalent cause of death from cancer, with projections indicating approximately 2.2 million new instances and 1.8 million deaths worldwide (Sung et al., 2021). In China, the primary treatment options for lung cancer include surgical intervention, radiation treatment, chemotherapy, precision cancer therapies, immune system treatments, and traditional Chinese medicine (Yang et al., 2018; Chaft et al., 2016). Recent reports suggest that luteolin may be a novel and potent agent against lung cancer with the potential to inhibit disease progression (Imran et al., 2019).

KRAS mutations are known to increase the expression of programmed death-ligand 1 (PD-L1) within tumor cells, enabling the tumor to shun the immune system for detection and subsequent destruction. An in vitro experiment demonstrated that luteolin inhibits the growth of KRAS-mutated cells in a dose-dependent manner. The expression of PD-L1 is a consequence of STAT3 activity, which engages the PD-L1 gene promoter upon phosphorylation. Luteolin inhibits the STAT3 signaling pathway and the expression of PD-L1, thereby exposing tumor cells to T cells of the immune system (Jiang et al., 2021; Watterson and Coelho, 2023). MiR-34a is commonly downregulated in cancer cells, and elevated levels of miR-34a have been shown to suppress tumor growth (Zhang et al., 2019; Fu et al., 2023). Research has indicated that luteolin upregulates the expression of miR-34a, which may subsequently inhibit the proliferation of non-small cell lung cancer (NSCLC) cells (Shi et al., 2014; Jiang et al., 2018). Circular RNAs (circRNAs) are upregulated in lung cancer tissues, and luteolin suppresses lung cancer progression by targeting the circ_0000190/miR-130a-3p/notch-1 signaling pathway (Zheng et al., 2023). Luteolin may inhibit the proliferation and migration of A549 cells by reducing the expression of AR and modulating the phosphorylation of AR receptor sites (Li X. et al., 2023).

The anticancer properties of luteolin have also been demonstrated through the induction of apoptosis in neoplastic cells (Çetinkaya and Baran, 2023). Luteolin induces mitochondria-dependent apoptosis in human lung adenocarcinoma cells (Chen et al., 2012). Luteolin promotes the activation of caspase-9 and caspase-3, decreases the expression of Bcl-2, increases the expression of BAX, increases the BAX/Bcl-2 ratio, and induces apoptosis by activating intrinsic pathways (Chen et al., 2012). Additionally, the accumulation of ROS induced by luteolin can enliven the extrinsic pathways modeled by TNF-induced signaling (Ju et al., 2007). Luteolin has been demonstrated to inhibit EMT and downregulate E-cadherin by suppressing the triggering of key signaling pathways, such as TGF-β1 and the PI3K/AKT-NF-κB-Snail pathways (Chen et al., 2013). Furthermore, Masraksa and colleagues have demonstrated that luteolin can hinder the spread and invasion of lung cancer cells by targeting the signaling pathways of focal adhesion kinase and non-receptor tyrosine kinase (Src/FAK) as well as its downstream pathways involving Ras-related C3 botulinum toxin substrate 1 (Rac1), cell division cycle 42 (Cdc42), and ras homologous gene family member A (RhoA) (Masraksa et al., 2020). Luteolin works synergistically with osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), to overcome acquired resistance in NSCLC cells by suppressing the hepatocyte growth factor (HGF)-MET-Akt signaling cascade, which is involved in MET amplification and hyperactivation (Huang G. et al., 2023). When used alone or in combination with factor-related apoptosis-inducing ligand (TRAIL), a novel and potent anticancer agent, can enhance the expression of death receptor 5 (DR5) and promote dynamin-related protein 1 (Drp1)-dependent mitochondrial fission. By increasing DR5 expression and Drp1-mediated mitochondrial fission, luteolin enhances the sensitivity of NSCLC cells to TRAIL (Wu et al., 2020). Another study indicated that LIM Kinase 1 (LIMK1) is a target of luteolin, which suppresses tumor growth by inhibiting LIMK1 activity (Zhang M. et al., 2021). Beyond its anticancer characteristics, luteolin also possesses the ability to alleviate bone cancer pain (Zhou et al., 2022). Luteolin involves numerous determinants and cascades related to lung cancer progression (Rakoczy et al., 2023). In summary, luteolin has shown potential as a therapeutic agent for lung cancer by affecting multiple key factors in disease progression, and further research into its clinical applications is warranted (Table 3). Luteolin has shown the potential to inhibit lung cancer progression by affecting various key tumor biological pathways. We believe that these mechanisms of action provide a scientific basis for luteolin as a candidate drug for lung cancer treatment. Future research should focus on clinical trials of luteolin and optimizing its efficacy through drug delivery systems.