Inflammation is a key driver of PF initiation and progression. Chemical agents, airborne pollutants, and pathogens elicit pulmonary inflammation characterized by inflammatory cell infiltration of alveoli, activation of pro-inflammatory signaling pathways, and robust production of mediators such as TNF-α, IL-1β, and IL-6—events integral to fibrogenesis (Racanelli et al., 2018; Wang et al., 2022). Multiple studies demonstrate that PD markedly suppresses activation of inflammatory cascades and the release of pro-inflammatory cytokines, thereby attenuating lung inflammation and mitigating fibrosis. In bleomycin-induced PF rat models, Qiu and colleagues, as well as Yang and colleagues (Qiu et al., 2019; Yang et al., 2023), independently showed that PD targets and inhibits the TNF signaling pathway, reduces alveolitis pathology scores, decreases leukocyte infiltration, collagen deposition, and hydroxyproline accumulation, and downregulates TNF-α, IL-1β, IL-6, and IL-17, thereby alleviating inflammatory injury and slowing fibrotic progression.

These anti-inflammatory effects have also been corroborated in vitro. In a paraquat injury model using MRC-5 human embryonic lung fibroblasts, Fu et al. (2020) reported that PD dose-dependently inhibited expression of NLRP3 inflammasome-related proteins (NLRP3, caspase-1, and ASC) and lowered levels of TNF-α, TGF-β, IL-1β, and IL-6, with the most pronounced effect at 100 μmol/L PD. Beyond chemically induced PF, PD also mitigates fibrosis triggered by physical toxicants. In a silica-induced silicosis rat model, Wu et al. (2025) found that PD suppressed TNF signaling and significantly reduced protein and mRNA expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and apoptosis-related targets (p53, caspase-3), thereby retarding fibrotic progression. Importantly, PD exerts protective effects against pathogen-associated pulmonary inflammation and subsequent fibrosis: in a Mycoplasma pneumoniae infection model, Tang et al. (2019) demonstrated that PD dampened aberrant activation of the NLRP3 inflammasome and NF-κB pathways, curtailed inflammatory mediator expression, and alleviated inflammation-related lung injury and fibrosis. Collectively, PD effectively counteracts inflammation-driven fibrogenesis across toxicant- and pathogen-induced settings, largely through modulation of TNF and NF-κB signaling and suppression of pro-inflammatory cytokine release.

Physiological redox homeostasis reflects a dynamic balance between oxidant generation and antioxidant defenses. When this balance is disrupted and reactive oxygen species (ROS) accumulate beyond the scavenging capacity of antioxidant systems, oxidative stress ensues, leading to cytotoxicity and tissue damage. Substantial evidence implicates oxidative stress in the pathogenesis of PF and other disorders such as diabetes and cardiovascular disease (Alfadda and Sallam, 2012; Otoupalova et al., 2020). PD enhances antioxidant capacity through multiple pathways, thereby reducing ROS burden, mitigating oxidative injury, and slowing PF progression. In a radon exposure-induced PF model, PD inhibited the PI3K/AKT/mTOR pathway, significantly decreased epithelial ROS levels, increased superoxide dismutase (SOD) activity in cells and mouse serum, and lowered serum malondialdehyde (MDA) (Chen et al., 2023). PD’s antioxidant effects were further validated in bleomycin-challenged Sprague-Dawley rats: Liu et al. (2020) showed that PD targeted the TGF-β1/Smad/ERK axis, elevated SOD activity, and reduced MDA and myeloperoxidase (MPO), with the high-dose PD group (160 mg/kg) achieving efficacy comparable to the reference drug pirfenidone. Additionally, in a model of inhalational exposure to artificially generated PM2.5 (aPM2.5), Yan et al. (2017) found that PD activated the pulmonary Nrf2/PPAR-γ axis, decreased the oxidative potential (OP) of aPM2.5, suppressed ROS production, and increased glutathione peroxidase (GSH-Px) activity, thereby strengthening cellular resilience to oxidative stress, reducing lung injury, and delaying fibrotic development.

EMT—the conversion of epithelial cells into motile mesenchymal cells—is a pivotal pathological process in PF(Chapman, 2011). PD inhibits EMT via several signaling routes, thereby restraining fibrotic progression. Within the TGF-β1/Smad/ERK pathway, PD reduces TGF-β1 expression, lowers Smad2 and Smad3 levels, and diminishes production of type I and III collagen and their procollagen propeptides (PICP and PIIINP). PD also decreases markers associated with matrix deposition and myofibroblast activation (hydroxyproline, α-SMA) while restoring E-cadherin, collectively suppressing EMT. Notably, at high dose (160 mg/kg), PD achieved a 17.5% inhibition of TGF-β1—exceeding the 12.3% observed with pirfenidone in the referenced studies (Liu et al., 2020; Qiu et al., 2019).

Through the PI3K/AKT/mTOR pathway, PD inhibits phosphorylation of PI3K, AKT, and mTOR, downregulates mesenchymal markers (FN1, vimentin), blocks EMT progression, and reduces collagen fiber deposition (Chen et al., 2023; Zhang et al., 2025). PD also coordinates additional pathways to suppress EMT and fibrosis: in an interstitial lung disease (ILD) mouse model, Zhang et al. (2024a) reported that PD activated AMPK/PGC-1α/PPARγ signaling while inhibiting HMGB1/RAGE signaling, thereby reducing aberrant expression of HMGB1, RAGE, SEPTIN4, ACTA2, and ITGAV and jointly repressing EMT and fibrotic responses. Consistently, Zeng et al. (2019) demonstrated that PD promoted Nrf2-mediated antioxidant defenses, decreased ROS and TGF-β1 levels, reversed TGF-β1-induced EMT, and ameliorated pulmonary fibrosis.

The onset and progression of PF are closely linked to dysbiosis and metabolic perturbations of the intestinal microbiota (Dong et al., 2024). PD improves PF by modulating the lung-gut axis, reshaping microbial communities, and altering their metabolites. In a bleomycin-induced PF model in C57BL/6 mice, Yang et al. (2023) showed that PD significantly increased the abundance of beneficial taxa (Muribaculaceae, Lactobacillus, Akkermansia) and promoted the expansion of probiotic genera such as Dubosiella, thereby remodeling the microbial ecosystem and attenuating PF. In a silica-induced silicosis model in Sprague-Dawley rats, Wu et al. (2025) further demonstrated that PD reversed the aberrant elevation of α diversity, decreased the relative abundance of phyla such as Elusimicrobiota, and increased levels of short-chain fatty acids (SCFAs) including propionate and acetate in colonic contents. SCFAs are key microbial metabolites with immunoregulatory and anti-inflammatory functions; perturbations in the gut microbiota-SCFA network correlate with the severity of lung injury. These findings suggest that PD exerts anti-fibrotic effects, at least in part, by modulating the gut microbiota-immune-metabolic axis.

In summary, PD is a pleiotropic natural compound that combats PF through convergent mechanisms—reprogramming inflammatory networks, counteracting oxidative stress, inhibiting EMT, and remodeling the intestinal microbiota. Across multiple PF models, PD has shown efficacy in preclinical models that is comparable to, and in some instances approaches or exceeds, that of standard-of-care agents in these experimental settings, with a favorable safety profile. These converging lines of evidence underscore PD’s therapeutic value and translational potential in PF (Figure 3).

Runaway inflammation is the central pathophysiological driver of ALI/ARDS; excessive activation of inflammatory cascades precipitates diffuse lung injury and respiratory failure (Bos and Ware, 2022). Across diverse ALI models, PD’s anti-inflammatory protection has been validated and linked to modulation of key signaling pathways. In a lipopolysaccharide (LPS)-induced rat ALI model, Li et al. (2014a) showed that PD significantly reduced levels of pro-inflammatory mediators—including TNF-α, IL-6, IL-1β, and high mobility group box 1 (HMGB1)—in bronchoalveolar lavage fluid (BALF) and serum, decreased myeloperoxidase (MPO) activity in lung tissue, and lowered neutrophil counts and protein content in BALF, thereby attenuating inflammatory lung injury (Li et al., 2014a; Li et al., 2014b). In the LPS-induced ALI model in BALB/c mice and BEAS-2B human bronchial epithelial cells, Jiang et al. further demonstrated that PD dose-dependently downregulated IL-1β, IL-6, IL-8, and TNF-α. Mechanistically, PD interrupted TLR4-MyD88-NF-κB signaling by downregulating Toll-like receptor 4 (TLR4) and its adaptor myeloid differentiation primary response protein 88 (MyD88), suppressing phosphorylation of IκB kinase (IKK) and IκBα, and thereby preventing NF-κB nuclear translocation and transcriptional activation (Jiang et al., 2015). In a cecal ligation and puncture (CLP) sepsis-induced ALI model, Liao et al. confirmed PD’s suppression of these cytokines in vivo, and complementary in vitro data implicated downregulation of the transcription factor Spi-B as an upstream mechanism by which PD restrains activation of the PI3K/AKT and NF-κB pathways (Liao et al., 2023).

An imbalance between oxidant production and antioxidant defenses is a second major contributor to lung injury, amplifying oxidative stress and pathological damage (Wang et al., 2025). PD exhibits robust control over redox homeostasis by activating endogenous antioxidant systems. In multiple models—including LPS-induced ALI, radiation injury, and radon exposure—PD significantly decreased lipid peroxidation products (LPO), malondialdehyde (MDA), and intracellular reactive oxygen species (ROS), while increasing superoxide dismutase (SOD) activity, thereby restoring the oxidant-antioxidant balance and limiting oxidative damage. In BEAS-2B cells and a murine thoracic irradiation model, Cao et al. (2017) found that PD activated the Sirt3-Nrf2/PGC-1α regulatory axis, augmenting pulmonary antioxidant defenses at the pathway level. In a radon exposure model, Chen et al. reported that PD downregulated phosphorylated AKT and mTOR in radon-exposed bronchial epithelial cells (BEAS-2B, 16HBE) and reduced phosphorylated PI3K in lung tissue of exposed mice; by suppressing aberrant PI3K/AKT/mTOR activation, PD curtailed upstream drivers of persistent oxidative stress (Chen et al., 2023). Moreover, in LPS-challenged RAW 264.7 cells and a Pseudomonas aeruginosa PA14 infection model, Chi et al. showed that PD directly bound the DLG motif of Nrf2, disrupted the KEAP1-Nrf2 interaction, inhibited Nrf2 ubiquitination and degradation, and promoted Nrf2 nuclear translocation, thereby inducing antioxidant response element (ARE)-regulated genes such as HO-1 and GCLC and strengthening global cellular antioxidant capacity (Chi et al., 2024). Together, these findings indicate that PD engages multiple nodes—Sirt3-Nrf2/PGC-1α, Nrf2, and PI3K/AKT/mTOR—to enhance resistance to oxidative stress in the injured lung.

Excessive apoptosis of alveolar epithelial and endothelial cells is pivotal to alveolar-capillary barrier failure (Gregoire et al., 2018). PD mitigates apoptosis by modulating Bcl-2 family proteins to stabilize the mitochondrial membrane. In burn- and LPS-induced rat ALI models, PD markedly upregulated anti-apoptotic Bcl-2 and Bcl-xL while downregulating pro-apoptotic Bax; this shift reduced mitochondrial release of cytochrome c (CYCS), suppressed activation of caspase-3, and significantly decreased the number of TUNEL-positive apoptotic cells, thereby preserving lung structural integrity (Li et al., 2014a; Li et al., 2014b). Complementing its anti-oxidative actions, PD also curtailed apoptosis in radon-exposed ALI cells by blocking PI3K/AKT/mTOR signaling (Chen et al., 2023). In LPS-induced ARDS models in vivo and in vitro, Li et al. (2019) further showed that PD promoted translocation of the E3 ubiquitin ligase Parkin from the cytosol to damaged mitochondria, activating mitophagy to clear dysfunctional organelles, dampen mitochondria-dependent apoptotic signaling, and enhance cellular resilience to injury.

Beyond anti-inflammatory, antioxidant, and anti-apoptotic effects, PD exerts additional protective actions in ALI. Shu et al. reported that PD dose-dependently increased the expression of club cell secretory protein (CCSP; also known as SCGB1A1) in lung tissue and bronchial epithelial cells and inhibited phospholipase A2 (PLA2) activity. These changes reduced degradation of pulmonary surfactant and formation of inflammatory lipid mediators, ultimately lowering pulmonary microvascular permeability and alleviating edema (Shiyu et al., 2011). In a mouse model of traumatic brain injury (TBI)-associated ALI, Gu et al. (2021) found that PD downregulated the damage-associated molecular pattern (DAMP) molecule S100B, thereby suppressing formation of neutrophil extracellular traps (NETs), mitigating NET-driven hyperinflammation and vascular leak. This mechanism interrupts a key pathogenic link along the brain-lung axis and provides a molecular basis for PD’s efficacy in ALI secondary to neurotrauma.

In sum, current evidence delineates PD as a multitarget natural compound capable of systemically recalibrating the complex pathophysiological networks underpinning ALI/ARDS. Through concurrent modulation of inflammatory signaling, reinforcement of endogenous antioxidant defenses, suppression of apoptosis with promotion of mitophagy, and additional barrier protective effects, PD shows substantial promise for the prevention and treatment of ALI/ARDS (Figure 4).

The core pathogenesis of viral pneumonia involves robust intrahost viral replication following cell entry, accompanied by excessive inflammation and programmed cell death, culminating in lung injury. PD exerts both direct antiviral effects and immune modulation, achieving synergistic antiviral and anti-inflammatory outcomes. Xu et al. (2021) identified PD as a putative broad-spectrum coronavirus inhibitor that effectively suppresses the proteolytic activities of SARS-CoV-2 and MERS-CoV 3-chymotrypsin-like protease (3CLpro)/main protease (Mpro) and papain-like protease (PLpro), thereby blocking viral replication. De Angelis et al. (2021) further showed that PD interferes with the viral transcription-replication program to inhibit viral protein synthesis, conferring marked antiviral and anti-inflammatory effects against influenza A virus and SARS-CoV-2 in vitro. In addition, Sun et al. (2022) elucidated PD’s protection against virus-induced cellular injury: SARS-CoV-2 nonstructural protein NSP6 binds ATP6AP1, impairing lysosomal acidification and arresting autophagic flux, which activates the NLRP3/ASC-dependent caspase-1 pathway, triggers pyroptosis of pulmonary epithelial cells, and promotes IL-1β/IL-18 release. PD targets this cascade by restoring autophagolysosomal function, suppressing pyroptosis and hyperinflammation, and thereby mitigating virus-mediated tissue damage.

In bacterial pneumonia, PD primarily acts by reprogramming inflammatory signaling and oxidative-stress responses, dampening the excessive host inflammation elicited by bacterial components and reducing parenchymal injury. S. aureus is a common HAP pathogen; its cell-wall lipoteichoic acid (LTA) is a key virulence factor. Using RAW 264.7 macrophages and BALB/c mice, Zhao et al. (2017) showed that LTA activates Toll-like receptor 2 (TLR2) to drive NF-κB signaling, resulting in overproduction of pro-inflammatory mediators (TNF-α, IL-1β, IL-6). PD attenuated this response in a dose-dependent manner by inhibiting the TLR2/MyD88/NF-κB axis and reducing nuclear translocation of NF-κB p65, thereby markedly suppressing LTA-induced inflammation. Zhao et al. further found that LTA induces excessive intracellular reactive oxygen species (ROS) and activates the caspase-9/3 cascade, leading to apoptosis. PD pretreatment lowered LTA-induced ROS, restrained NF-κB nuclear translocation, and reduced caspase-9/3 activation and apoptosis. Collectively, PD combats bacterial pneumonia via dual modulation of inflammatory pathways and oxidative stress.

Mycoplasma spp. lack a cell wall and use adhesins to bind host cell-surface receptors, activating inflammatory signaling and inducing cellular injury; chronic or unresolved infection may promote pulmonary fibrosis. PD targets key pathogenic pathways of Mycoplasma, suppressing infection-induced inflammation and pyroptosis while helping prevent subsequent fibrotic remodeling. In BEAS-2B cells and BALB/c mice, Chen et al. (2023) showed that Mycoplasma pneumoniae (MP) activates caspase-1, generating the N-terminal fragment of gasdermin D (GSDMD-N) that forms membrane pores, thereby causing pyroptosis and robust release of IL-1β, IL-18, and lactate dehydrogenase (LDH). PD inhibited this caspase-1/GSDMD pathway in a dose-dependent fashion, reducing GSDMD-N formation and cytokine release, and significantly alleviating MP-induced epithelial pyroptosis and lung injury in vitro and in vivo. Given the long-term risk of fibrosis, Tang et al. combined in vivo and in vitro analyses and found that PD protects against MP pneumonia (MPP) by suppressing activation of the NLRP3 inflammasome (NLR family pyrin domain-containing 3) and the nuclear factor-κB (NF-κB) pathway, thereby constraining post-infection pulmonary inflammation and fibrotic progression. Consistent benefits were also observed in Mycoplasma gallisepticum (MG) models. Zou et al. (2020) demonstrated that PD dose-dependently inhibited MG growth in vitro, restored MG-suppressed viability of DF-1 cells, and reversed MG-induced G1 cell-cycle arrest and apoptosis. In vivo, PD ameliorated MG-driven inflammatory cell infiltration, epithelial desquamation, and interstitial congestion in embryonic chicken lungs, while inhibiting TLR6/MyD88/NF-κB activation and downstream cytokine secretion. Notably, its efficacy was comparable to that of the macrolide antibiotic tylosin.

In sum, PD exhibits favorable therapeutic effects against pneumonia caused by viruses, bacteria, and Mycoplasma by virtue of its multi-target profile. Its additional advantages-low toxicity, broad-spectrum activity, and a promising resistance profile-position PD as a compelling candidate for pneumonia therapy and a potential adjunct to existing antimicrobial regimens (Figure 5).

Suppressing cancer-cell proliferation and triggering programmed cell death are central mechanisms of PD’s anti-LC activity. In a concentration-dependent manner, PD markedly reduces the viability of multiple non-small cell lung cancer (NSCLC) cell lines, including A549 and NCI-H1975. In A549 cells, PD induces DNA damage and cellular senescence and ultimately apoptosis, thereby exerting antitumor effects (Verma and Tiku, 2022). Consistently, PD inhibits A549 and NCI-H1975 proliferation in a dose- and time-dependent fashion, induces apoptosis, and causes S-phase arrest, thereby preventing cell-cycle progression (Zhang et al., 2014). Complementing these findings, in vitro and in vivo studies show that PD suppresses the invasive and proliferative capacities of Lewis lung carcinoma (LLC; a murine NSCLC model) and downregulates epidermal growth factor receptor (EGFR) and tumor necrosis factor (TNF) protein expression, collectively restraining NSCLC tumor growth (Fan and Shuai, 2024).

Beyond direct cytotoxicity, PD modulates the TME and antitumor immune responses. Inflammation and immune suppression within the TME are key drivers of lung cancer progression. PD attenuates these processes by inhibiting pro-inflammatory signaling and lowering cytokine expression. Given the pivotal role of NF-κB activation in malignant progression, studies using human LC cell lines A549 and H1299 demonstrate that PD suppresses NF-κB signaling in a dose-dependent manner, downregulates NLRP3 inflammasome activation, and reduces the release of IL-1β and IL-18. This reprograms the immunosuppressive TME and curtails proliferation, migration, and invasion of A549 and H1299 cells (Zou et al., 2018). These observations suggest that PD not only directly restrains tumor cells but may also potentiate antitumor immunity, providing a mechanistic rationale for combination with immunotherapy.

In NSCLC models, PD enhances cisplatin-induced apoptosis by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and the JNK/p38 MAPK pathway (Wu et al., 2024). This effect requires PD-driven upregulation of NADPH oxidase 5 (NOX5); NOX5 knockout attenuates PD-mediated ROS cytotoxicity, and xenograft studies corroborate the combinatorial antitumor efficacy.

In a prospective pilot study, prophylactic topical 1.5% polydatin cream reduced the incidence of afatinib-associated rash to 41.2%, with no grade-3 events and no treatment discontinuations due to dermatologic toxicity. Efficacy was comparable to tetracyclines and was achieved without additional adverse effects (Fuggetta et al., 2019). These data suggest that PD—via modulation of the EGFR axis and local anti-inflammatory activity—can alleviate EGFR-inhibitor skin toxicity and improve patients’ quality of life.

PD functions as a radiosensitizer in lung cancer, enhancing tumor radiosensitivity while attenuating RT-induced B-cell infiltration and inflammatory responses, thereby reducing normal-tissue injury (Guo et al., 2023). In animal models, PD plus RT significantly decreases tumor volume with concomitantly less collateral tissue damage, indicating improved therapeutic index and favorable safety.

In sum, PD’s antitumor efficacy against lung cancer is supported by convergent evidence: it suppresses proliferation, induces apoptosis, and reconditions the TME, while synergizing with chemotherapy, targeted therapy, and RT. Nevertheless, poor aqueous solubility and low oral bioavailability remain barriers to clinical translation. Formulation and delivery innovations are addressing these limitations. For example, cocrystallization of PD with L-proline (PD-L-Pro) increased solubility and dissolution rate by approximately 15.8% and preserved potent cytotoxicity against A549 cells while significantly reducing toxicity toward normal HEK-293 cells (Lou et al., 2021). In parallel, nanodelivery systems have been engineered to enhance targeting and exposure: layer-by-layer-assembled, hyaluronic acid/lactoferrin dual-coated, PD-loaded PLGA nanoparticles actively target CD44 receptors on lung cancer cells, improve cellular uptake, and augment antitumor activity, while also enhancing PD’s solubility and stability (Nashaat et al., 2024). Collectively, these strategies mitigate pharmacokinetic liabilities and improve specificity and safety, charting a feasible path from bench to bedside and broadening the therapeutic horizon for PD in lung cancer (Figure 6).

PD exhibits pronounced anti-inflammatory and antioxidant activities and has shown substantial therapeutic potential in asthma models, with mechanisms validated across multiple experimental dimensions.

In an asthmatic mouse model, Hanna et al. (2019) reported that PD alleviated airway inflammation by downregulating pulmonary surfactant protein-D (SP-D) and urocortin (UCN). PD also significantly reduced serum immunoglobulin E (IgE) and decreased the expression of key cytokines (IL-4, IL-5, IL-13, IFN-γ, and TNF-α). Concomitantly, PD restored redox balance—lowering malondialdehyde (MDA) while elevating glutathione (GSH) and superoxide dismutase (SOD) activities. Histopathological assessment corroborated these findings: PD improved airway architecture and reduced inflammatory cell infiltration, with efficacy comparable to dexamethasone.

Using in vitro and in vivo approaches, Zeng et al. (2019) demonstrated that PD activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, thereby enhancing cellular antioxidant capacity. Nrf2 activation upregulated downstream cytoprotective enzymes heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced reactive oxygen species (ROS) accumulation, and diminished the release of transforming growth factor-β1 (TGF-β1), effectively mitigating oxidative stress. Notably, the antioxidant action of PD was markedly attenuated in Nrf2-deficient cellular models, underscoring the centrality of Nrf2 signaling to PD’s mechanism (Huang et al., 2015).

Ferroptosis and ferritinophagy are critical regulatory nodes in asthma progression, and their aberrant activation is closely associated with disease exacerbation (Li et al., 2023). In an ovalbumin (OVA)-induced rat model, Li et al. (2025) showed that PD suppresses NCOA4-mediated ferritinophagy, thereby limiting Fe²⁺ release and preventing ferroptotic injury in lung tissue; PD also reduced intrapulmonary ferritin deposition. Through these coordinated actions, PD significantly attenuated airway inflammation, improved pulmonary function, and alleviated airway remodeling, yielding meaningful disease modification.

Mast cells are pivotal in asthma pathobiology and constitute an important therapeutic target (Joulia et al., 2024). In vivo, Yuan et al. (2012) found that PD downregulated UCN expression, blocked Ca²⁺ influx, and inhibited mast-cell degranulation—mechanisms that further expand the spectrum of PD’s anti-asthmatic activities.

In sum, PD exerts clear therapeutic effects in asthma via multidimensional and synergistic mechanisms. It activates the Nrf2/HO-1 axis to curb oxidative stress, lowers pro-inflammatory cytokine levels, and suppresses UCN expression and mast-cell degranulation to relieve airway inflammation. In parallel, PD modulates ferritinophagy and ferroptosis to correct iron-handling abnormalities, thereby further limiting airway remodeling and improving lung function. These integrated actions highlight PD’s unique advantages and translational potential in the treatment of asthma (Figure 7).