Viral pneumonia—principally caused by influenza viruses, coronaviruses, and related pathogens—is an inflammatory condition of the lung in which direct viral injury to the alveolar epithelium, coupled with an exaggerated host immune response, leads to impaired gas exchange and, in severe cases, multi-organ failure (Figueiredo, 2009; Ruuskanen et al., 2011; Febbo et al., 2024). As the fundamental pathological event underlying influenza, Coronavirus Disease 2019(COVID-19), and other major respiratory illnesses, viral pneumonia is the primary cause of mortality in acute respiratory infections and predisposes survivors to secondary bacterial infections or chronic pulmonary fibrosis, thereby increasing clinical complexity (Lee et al., 2016; Rasool et al., 2024). The latest data indicate that viruses are responsible for exceeding 30% of community-acquired pneumonia cases worldwide (Ruuskanen et al., 2011; Jain et al., 2015). During the COVID-19 pandemic, the mortality rate among severely ill patients exceeded 10% at one point, causing a profound impact on healthcare systems and the economy (Richardson et al., 2020; Zhou et al., 2020). In the face of continual viral mutation and immune evasion, combined anti-inflammatory and antioxidant therapy has become crucial for improving outcomes (Cecchini and Cecchini, 2020; Suhail et al., 2020). The development of precise immunomodulatory and tissue-repair strategies constitutes an urgent research priority.

Inflammation and oxidative stress are the core pathological features of viral pneumonia: after viral invasion, on the one hand, it activates immune cells (such as macrophages and neutrophils) to release pro-inflammatory factors, such as interleukin-6(IL-6) and tumor necrosis factor-alpha (TNF-α), triggering a “cytokine storm”, leading to the destruction of the alveolar-capillary barrier and pulmonary edema; on the other hand, viral replication and inflammatory responses induce excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), causing lipid peroxidation, deoxyribonucleic acid (DNA) damage and mitochondrial dysfunction, further aggravating tissue oxidative damage (Cecchini and Cecchini, 2020; Merad and Martin, 2020; Suhail et al., 2020; Ye et al., 2020). The two form a vicious cycle through mutual amplification: inflammatory signals drive ROS production, while oxidative stress activates pathways such as the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, promoting the spread of inflammation (Suhail et al., 2020). This synergistic effect not only intensifies alveolar epithelial cell apoptosis and pulmonary interstitial fibrosis but also triggers systemic multi-organ damage and failure, constituting the key mechanism for the high mortality rate of viral pneumonia. The inflammatory and oxidative stress responses involved in the development of viral pneumonia are related to abnormalities in several signaling pathways. Viral infection activates inflammatory pathways through pattern recognition receptors, leading to atypical high expression of pro-inflammatory factors, while the inflammatory cascade exacerbates oxidative stress and mitochondrial dysfunction (Merad and Martin, 2020). The bidirectional vicious cycle of “inflammation-oxidative stress” becomes the pathogenesis of viral pneumonia (Figure 1). This article reviews the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, NLRP3 inflammasome signaling pathway, etc., involved in the pathological process of viral pneumonia. It emphasizes the core molecular structures of the above pathways, their dynamic interactions, and their key roles in alveolar epithelial apoptosis, immune imbalance, and pulmonary fibrosis, providing a theoretical basis and new therapeutic strategies for targeted inhibition of the inflammatory storm and restoration of redox homeostasis (Figure 2).

The most widely used Western medicines for viral pneumonia are oseltamivir and remdesivir. Oseltamivir inhibits influenza neuraminidase and thus blocks viral release from host cells, whereas remdesivir, a ribonucleic acid (RNA)-dependent RNA-polymerase inhibitor, interferes with the replication of coronaviruses and other RNA viruses (Thorlund et al., 2011). Prolonged use of these drugs, however, is limited by high cost, emerging resistance, and adverse effects (notably gastrointestinal reactions and hepato-renal dysfunction), highlighting the need for safer and more economical alternatives (Thorlund et al., 2011). Traditional Chinese Medicine (TCM), with its multicomponent, multitarget characteristics, offers unique advantages in modulating inflammation and oxidative stress. Active ingredients such as baicalin and quercetin attenuate lung injury by suppressing NF-κB and NLRP3 inflammasome activation while simultaneously inducing Nrf2-mediated antioxidant defences with relatively low toxicity (Sul and Ra, 2021; Shen et al., 2023; Wen et al., 2023). During the COVID-19 pandemic, several clinical studies have confirmed the therapeutic potential of TCM formulations. For example, a multicenter randomized controlled trial showed that Lianhua Qingwen significantly shortened the duration of fever, cough, and fatigue in patients with mild to moderate COVID-19, while reducing radiographic lung lesion progression compared to control treatment (Zhan et al., 2023). Similarly, Xuebijing injection, in a real-world cohort study, was associated with improved oxygenation index, reduced IL-6 levels, and lower mortality in severe COVID-19 cases (Luo et al., 2020). These findings highlight the potential of TCM as an adjunct to conventional therapy in managing viral pneumonia. Nevertheless, the complex chemical composition of herbal formulae and their multi-pathway actions remain incompletely characterised, and systematic investigation of individual natural products is still inadequate. To address this, we conducted a systematic literature search using PubMed, Web of Science, and SciFinder, focusing primarily on studies published within the past 10 years. Additionally, a few earlier seminal studies were included due to their foundational contributions to the understanding of compound–target–pathway interactions in viral pneumonia. The search strategy employed combinations of keywords including “viral pneumonia,” “traditional Chinese medicine,” “natural product,” “inflammation,” and “oxidative stress,” along with mechanism-related terms such as “NF-κB,” “Nrf2,” “PI3K/Akt,” “MAPK,” and “NLRP3 inflammasome” to ensure accurate and relevant retrieval. Based on this systematic review of the literature, this article summarizes current advances in the modulation of inflammation–oxidative stress networks by natural products and elucidates their compound–target–pathway interactions, thus providing theoretical foundations and innovative therapeutic perspectives for the treatment of viral pneumonia (Table 1; Figure 3).

TCM natural products in treating viral pneumonia lie in their “multi-target, multi-pathway” synergistic regulation of the inflammation-oxidative stress network, establishing a dynamic balance of “anti-inflammatory, antioxidant, and antiviral” effects (Zhang et al., 2025). These compounds primarily act on key signaling nodes, including NF-κB, Nrf2, PI3K/Akt, MAPK, and the NLRP3 inflammasome. To further elucidate the crosstalk mechanisms, several studies have identified shared molecular switches that integrate these pathways. For example, IKKβ not only mediates NF-κB activation but also interacts with Keap1, a redox-sensitive regulator of Nrf2, thereby linking oxidative and inflammatory responses. PI3K/Akt signaling promotes Nrf2 nuclear translocation and antioxidant gene expression, while reducing intracellular ROS and indirectly suppressing both NF-κB and NLRP3 activation. Natural products such as curcumin inhibit IKKβ and covalently modify cysteine residues on Keap1, thus activating Nrf2 and blocking inflammatory transcription (Rahban et al., 2020). Similarly, berberine activates PI3K/Akt signaling, stabilizes Nrf2, and concurrently downregulates NF-κB activity (Zhang et al., 2016). These findings exemplify how natural compounds can coordinate multi-pathway regulation through critical signal convergence hubs, achieving redox–immune homeostasis. Despite structural diversity, compounds from different chemical classes—including flavonoids, polyphenols, terpenoids, alkaloids, anthraquinones, lignans, and polysaccharides—often converge mechanistically (Daskou et al., 2023; Guo et al., 2024). For instance, flavonoids (e.g., isoquercitrin, kaempferol, baicalin, hesperetin) and polyphenols (e.g., rosmarinic acid, resveratrol, theaflavin-3′-gallate, proanthocyanidins) consistently suppress NF-κB-mediated cytokine production and activate Nrf2 signaling, often via their antioxidant and free radical-scavenging properties (Lee et al., 2017; Li et al., 2020; Arjsri et al., 2022; Luo et al., 2023; Shen et al., 2023; Sima et al., 2023; Sun et al., 2023; Wang et al., 2024). Terpenoids (e.g., andrographolide, patchouli alcohol, artesunate) regulate multiple inflammatory axes—including TLR4/NF-κB, PI3K/Akt, JAK/STAT, and Nrf2—to modulate both immune activation and apoptosis (Ding et al., 2017; Yu et al., 2019; Zhou et al., 2022). Alkaloids like berberine, and anthraquinones like emodin, inhibit both NF-κB and MAPK signaling while modulating caspase-mediated apoptosis (Dai et al., 2017; Zhao et al., 2025). Lignans (e.g., phillyrin) and polysaccharides (e.g., astragalus polysaccharide) simultaneously target NLRP3, NF-κB, and Nrf2 to restore immune–redox balance (Zhang et al., 2023). These functional effects are closely associated with the compounds’ structural features. Shared pharmacophores—such as α,β-unsaturated carbonyls, hydroxyl-rich aromatic rings, and quaternary ammonium groups—facilitate simultaneous interactions with multiple inflammatory and oxidative signaling proteins (Bousquet et al., 2020; Fu et al., 2022). Moreover, physicochemical parameters like hydrophilicity, molecular size, and charge influence bioavailability, tissue distribution, and phase-specific efficacy. For example, hydrophilic polysaccharides and glycosylated flavonoids accumulate in alveolar fluid and are suited for mucosal inflammation, while lipophilic terpenoids and anthraquinones cross membranes more rapidly to target viral replication compartments or redox-sensitive proteins (Huang et al., 2022). This structure–function correspondence forms the mechanistic foundation for multi-target optimization and synergistic combination strategies in natural product–based antiviral drug development. However, even compounds sharing identical pharmacophores may exhibit divergent signaling behaviors due to differences in stereoelectronic properties and molecular frameworks. For example, both artesunate and andrographolide contain α,β-unsaturated carbonyl groups, yet their distinct backbone rigidity, hydrophobicity, and functional moieties confer different pathway preferences. Artesunate, with its endoperoxide bridge and potent ROS-modulating capacity, predominantly suppresses the NF-κB signaling pathway (Wang et al., 2017). In contrast, andrographolide, owing to its conjugated structure and electrophilicity, tends to modulate the MAPK cascade. In TNF-α–stimulated cells, andrographolide significantly inhibits the phosphorylation of p38 MAPK and ERK1/2, supporting its anti-inflammatory mechanism of action (Li et al., 2017). While these findings demonstrate robust regulatory activity across multiple pathways, key unresolved questions remain regarding their upstream specificity, timing, and viral context. Despite substantial progress in delineating the roles of NF-κB, Nrf2, PI3K/Akt, MAPK, and NLRP3 pathways, several mechanistic gaps remain. For example, the specific upstream regulators of distinct MAPK subtypes in viral pneumonia remain poorly defined. Similarly, the temporal and context-dependent dual roles of PI3K/Akt, which can support viral replication but also mediate anti-inflammatory signaling, warrant further investigation. Furthermore, the precise timing and regulation of NLRP3 inflammasome activation in balancing immune defense versus tissue injury is still not fully understood. Future studies should address these pathway-specific gaps to optimize therapeutic interventions.

In addition, the physicochemical characteristics of different classes of natural compounds—including hydrophilicity, lipophilicity, molecular size, and charge—substantially influence their tissue distribution and stage-specific therapeutic efficacy. Hydrophilic polysaccharides and glycosylated flavonoids diffuse efficiently into alveolar fluid, making them particularly suited for mitigating early-phase mucosal inflammation at the macrophage–epithelial interface. In contrast, lipophilic terpenoids and anthraquinones more readily penetrate cell membranes and accumulate in viral replication compartments or redox-sensitive targets. There, they may exert antiviral or anti-inflammatory effects by inducing ferroptosis or covalently modifying key regulators such as Keap1 and IKKβ via peroxide bridges or Michael addition (Orosco and Quimque, 2024; Guo et al., 2021; Kiser et al., 2021; Das et al., 2023; Zhao et al., 2024). Typically, small molecules act rapidly to scavenge ROS and suppress early inflammation, whereas macromolecules or saponins bearing sugar moieties tend to accumulate in immune cells and exert prolonged anti-cytokine effects (Jen et al., 2021; Shao et al., 2022; Shen et al., 2024). While structure–function regularities support the multitarget potential of natural products, their therapeutic effects are shaped by the specific biological context of each viral infection. Therefore, effective application of TCM-derived compounds in viral pneumonia requires careful consideration of pathogen-specific immune and oxidative response profiles. For instance, SARS-CoV-2 strongly activates the NLRP3 inflammasome, while H1N1 influenza virus preferentially stimulates NF-κB and MAPK cascades (Wang and Li, 2023). These mechanistic differences may underlie the virus-specific efficacy of certain natural compounds. Baicalin has been shown to inhibit NLRP3 activation and alleviate lung injury in SARS-CoV-2 models (Wang and Li, 2023). In contrast, resveratrol, a known NF-κB inhibitor, exhibits greater anti-inflammatory activity in H1N1-induced lung inflammation (Rossi et al., 2021). In addition, differences in viral entry mechanisms may influence how effectively natural compounds reach and modulate early intracellular signaling targets (Caffrey and Lavie, 2021; Jackson et al., 2022). These variations highlight the need for mechanistic validation in multiple viral infection models when assessing the therapeutic potential of multitarget agents. Building upon these mechanistic and physicochemical insights, it is also crucial to compare the broader pharmacological frameworks of natural products versus conventional Western medicines, especially in the context of antiviral therapy. Western antiviral agents such as oseltamivir and remdesivir exert rapid viral suppression by targeting specific viral proteins, with the advantages of well-defined mechanisms and direct onset of action. However, their clinical application remains challenged by narrow target specificity, the risk of resistance development, and limited capacity to modulate host-driven inflammatory responses. In contrast, natural products exhibit multi-target and holistic regulatory properties, showing potential in alleviating host inflammation and immune dysregulation associated with viral infections. Furthermore, recent studies have demonstrated the synergistic potential of combining natural products with Western medicines. For instance, baicalin has been reported to enhance the therapeutic efficacy of oseltamivir in influenza-infected mice by reducing proinflammatory cytokines, alleviating pulmonary inflammation, and improving survival outcome (Ding et al., 2014). Similarly, multi-component formulations such as Lianhua Qingwen have also been reported to potentiate the antiviral and anti-inflammatory effects of oseltamivir in influenza models, further supporting the rationale for integrative therapy approaches (Yang et al., 2020). These findings suggest that integrative treatment strategies may provide superior outcomes by simultaneously targeting viral replication and host immune dysregulation. As such, the inclusion of natural products in antiviral combination regimens represents a promising direction for clinical translation and personalized therapy.

Currently, natural products from TCM demonstrate multi-target synergistic advantages in regulating inflammation and oxidative stress to treat viral pneumonia, but their practical application still faces significant limitations. First, the development and industrialization of natural products are hindered by complex extraction and purification processes. The stability and consistency of bioactive compounds—such as alkaloids and saponins—are susceptible to variations in herbal source, harvesting season, and processing methods, resulting in batch-to-batch fluctuations and impeding standardization of formulation and quality control (Leong et al., 2020; Guo et al., 2025). Second, significant bottlenecks exist in the clinical translation of mechanistic studies. Most investigations are restricted to animal models or immortalized cell lines, which often fail to recapitulate the physiological behavior of primary human alveolar epithelial cells due to altered receptor expression, metabolic pathways, and redox dynamics. This limits the translatability of in vitro findings (Ma et al., 2024). Moreover, substantial species-specific differences in immune signaling between rodents and humans, including immune cell distribution, cytokine profiles, and kinase activity, further compromise the predictive value of animal studies. These cross-species discrepancies challenge both efficacy and toxicity extrapolation to clinical settings. To address these issues, future research should prioritize the use of human-relevant models, such as patient-derived lung organoids, and cross-species comparative transcriptomics (Leach et al., 2020; Tindle et al., 2021; Han et al., 2022). These platforms may provide more accurate insights into therapeutic mechanisms and safety profiles, thereby facilitating clinical translation of TCM-based interventions. Additionally, the potential toxicity of long-term administration on metabolic organs such as the liver and kidneys remains insufficiently evaluated. Moreover, few studies have systematically addressed the dose–effect–toxicity relationship, which is essential for defining the clinical safety profile of natural products. Many compounds exhibit narrow therapeutic windows, and increasing the dose beyond the effective range may lead to hepatic or renal toxicity (Kim et al., 2012). Notably, the effective dose for modulating inflammatory responses may differ from that required for direct antiviral effects, suggesting the need for dual-endpoint dose optimization. To enhance both safety and clinical translatability, future investigations should integrate pharmacokinetic and pharmacodynamic data, such as maximum plasma concentration, area under the concentration-time curve, and tissue distribution profiles, to precisely define the therapeutic window and optimize exposure levels. Such integrative strategies may help mitigate dose-related organ toxicities, particularly during long-term administration (Rombolà et al., 2020; Zagaliotis et al., 2022). Finally, current studies on the target mechanisms of natural medicines remain focused on common antiviral or inflammatory pathways, with limited exploration of virus-specific host interaction nodes (Chen and Ye, 2022).

Future research should prioritize the following directions to improve the translational feasibility of natural product–based therapies: On the one hand, integration of systems biology and artificial intelligence should be leveraged to construct multi-layered “component–target–pathway–disease” networks via network pharmacology. This would help elucidate spatiotemporal regulatory patterns of multi-component formulations on inflammation–oxidative stress axes, with functional validation in organoid or lung-on-chip models to better simulate tissue-level repair. On the other hand, clinical research must be deepened and refined. Large-scale, multi-center randomized controlled trials should be designed to evaluate the long-term impacts of natural products on pulmonary lesion resolution and organ function. These assessments can integrate metabolomics, advanced imaging, and biomarker-based stratification to support precision interventions. Importantly, formulation innovation should be grounded in the physicochemical limitations of natural products. For example, lipophilic terpenoids with poor membrane permeability may benefit from self-emulsifying drug delivery systems or solid lipid nanoparticles, while rapidly cleared polysaccharides may require chitosan-coated nanocarriers or polymeric conjugation to improve stability and bioavailability (Jörgensen et al., 2020; Guadarrama-Escobar et al., 2023; Kumar et al., 2025; Uttreja et al., 2025). Concurrently, synthetic biology can be employed to optimize the biosynthetic pathways for producing high-purity active ingredients under standardized quality control frameworks (Nasim et al., 2022). By integrating the holistic principles of TCM with modern precision medicine and pharmaceutical technology, it may be possible to overcome key bottlenecks in the clinical translation of natural medicines for viral pneumonia.