Research Progress of Paeonol in the Treatment of Respiratory Diseases

Abstract

Paeonol is a natural phenolic compound found in plants of the Ranunculaceae family, such as Mudanpi (Moutan Cortex) and Shaoyao (Paeoniae Radix). It possesses a wide range of pharmacological activities. Modern research confirms that paeonol exhibits various pharmacological effects, including anti-inflammatory, antioxidant, antitumor, and immunomodulatory activities, demonstrating unique application value in the treatment of respiratory diseases. With the recent development of nanodelivery systems and derivatives, issues such as low oral bioavailability, poor stability, and short half-life of paeonol have been significantly improved. This article systematically reviews the role and mechanisms of paeonol in treating respiratory diseases such as asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), lung cancer, allergic rhinitis, and pneumonia, analyzing existing application problems and potential solutions, aiming to provide a theoretical basis for its clinical application and further research and development.

Keywords

paeonol - respiratory diseases - review - pharmacological activity - Mudanpi (Moutan Cortex) - Shaoyao (Paeoniae Radix)

Introduction

Respiratory diseases represent a significant global public health problem with high mortality rates and substantial economic burden. They primarily include acute respiratory diseases such as pneumonia and influenza, as well as chronic respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, lung cancer, and tuberculosis.[1] Epidemiological studies indicate that the global number of asthma patients has reached 260.5 million; COPD ranks as the third leading cause of death worldwide, causing approximately 3.7 million deaths in 2021 alone; lung cancer continues to be the leading cause of cancer-related deaths, with approximately 2 million new cases and 1.76 million deaths annually; the incidence of pulmonary fibrosis and pulmonary hypertension, while relatively lower, shows an increasing trend.[2] Most of these chronic respiratory diseases are characterized by a long course and a tendency to recur, requiring long-term, standardized treatment, which imposes a heavy economic burden on patients and society.[3] Existing treatment methods cannot reverse the continuous progression of chronic respiratory diseases. Therefore, it is necessary to develop alternative therapeutic drugs.

Paeonol is mainly found in Chinese herbs such as Mudanpi (Moutan Cortex), Shaoyao (Paeoniae Radix), and Xuchangqing (Cynanchi Paniculati Radix et Rhizoma).[4] [5] Medicines rich in paeonol typically have the effects of clearing heat and cooling blood, promoting blood circulation and removing blood stasis, and can be used to treat various diseases. They play important roles in classic formulations such as Liuwei Dihuang Pill, Jingui Shenqi Pill, and Danggui Yangxue Pill.[6] Furthermore, they can be combined with other Chinese herbs like Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Chuanxiong (Chuanxiong Rhizoma), and Honghua (Carthami Flos) to further enhance the efficacy of promoting blood circulation and removing blood stasis. With the deepening of modern medical research on natural medicines, plant active ingredients show unique advantages in the treatment of respiratory diseases.[7] Modern pharmacological studies indicate that paeonol possesses multidimensional pharmacological activities, including anti-inflammatory, antibacterial, analgesic, cardiovascular-protective, and immunomodulatory effects. It has established a mature clinical application system in the field of topical preparations for skin diseases and also shows potential in adjuvant therapy for cardiovascular and cerebrovascular diseases and tumors.[8] [9] In recent years, with the continuous deepening of research on the pharmacological mechanism of paeonol, its application prospects as a multitarget natural phenolic compound in the treatment of respiratory diseases have gradually become prominent.[10] This article systematically reviews the mechanisms and research progress of paeonol in respiratory diseases such as asthma, COPD, and pulmonary fibrosis, aiming to explore its potential application value in the treatment of respiratory diseases and to provide a theoretical basis and research direction for developing new drugs for respiratory diseases.

Physicochemical Properties and Pharmacological Effects of Paeonol

Source and Physicochemical Properties of Paeonol

In traditional medical systems, traditional Chinese medicine has always been an important means for clinical disease treatment.[11] Modern research reveals that the therapeutic effects of Chinese herbs often stem from the natural active components they contain, which play key roles in maintaining organismal balance, regulating inflammatory responses, and improving disease states.[12] [13] Unlike single-target synthetic drugs, natural compounds typically possess comprehensive regulatory capabilities through multiple pathways and links, making them highly promising resources for new drug development.[14] [15] Paeonol (2′-Hydroxy-4′-methoxyacetophenone, C₉H₁₀O₃) is an abundantly available natural phenolic compound widely found in various plants. Paeonol is most abundant in Mudanpi (Moutan Cortex) and possesses various significant pharmacological effects[16]; the rhizome of Shaoyao (Paeoniae Radix) is relatively rich in paeonol[17]; the entire plant of Xuchuangqing (Cynanchi Paniculati Radix et Rhizoma) contains abundant paeonol.[18] Paeonol is a white crystalline powder with a molecular weight of 166.17, exhibiting a bitter and pungent taste. It possesses relative stability to temperature and light, displays typical lipophilic characteristics, is slightly soluble in water, and is readily soluble in organic solvents such as ethanol and acetone.[19] [20]

Modern pharmacological studies indicate that methods such as high-performance liquid chromatography (HPLC) can be used for the extraction and purification of paeonol from Mudanpi (Moutan Cortex), allowing for precise quantitative analysis of its content.[21] Pharmacokinetic studies show that paeonol is widely distributed in animal bodies, possesses good tissue permeability, and can cross the blood–brain barrier.[22]

Pharmacological Effects of Paeonol

Paeonol exhibits a wide range of pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects.[23] Paeonol can modulate the inflammatory microenvironment and accelerate periodontal tissue regeneration.[24] [25] Regarding its antitumor effects, paeonol exerts anti-ovarian cancer activity by activating autophagy in cancer cells, providing a new strategy for the treatment of ovarian cancer.[26] Furthermore, paeonol can alleviate cisplatin-induced nephrotoxicity, thereby reducing the harm of chemotherapy to cancer patients.[27] These broad pharmacological effects provide a solid scientific foundation for the application of paeonol in the treatment of various diseases. Further exploration of its mechanisms of action and optimization of its clinical application are warranted to fully realize paeonol's therapeutic potential.

Bioavailability and Pharmacokinetics of Paeonol

As a naturally derived active component, paeonol possesses good safety and low adverse reactions, providing an important safety guarantee for its clinical application.[28] Paeonol ointment is a non-hormonal topical preparation primarily used to relieve symptoms of inflammatory skin diseases such as eczema and dermatitis, as well as skin itching. Topical application of paeonol can significantly reduce skin inflammatory reactions, inhibit itching behavior, and achieve anti-inflammatory and antipruritic effects by regulating inflammatory mediators and immune responses, offering a safe alternative to traditional corticosteroid topical medications.[29] Studies on metabolic pathways indicate that paeonol can be rapidly metabolized in vivo to generate various metabolites, such as sulfate and glucuronide derivatives. These metabolites potentially enhance biological effects and are primarily excreted through urine.[30] [31]

Safety, Toxicity, and Side Effects of Paeonol

Although paeonol is derived from natural plants and has low toxicity, excessive use may still have effects on the body. Animal experiments confirm that paeonol has good safety within the effective dose range. The maximum tolerated dose of paeonol in female rats reached 5,000 mg·kg⁻¹ without significant toxic reactions,[31] indicating the potential clinical application value of paeonol as a natural therapeutic agent.

Role of Paeonol in Respiratory Diseases

Respiratory diseases, such as asthma, pneumonia, COPD, and pulmonary fibrosis, are common clinical conditions.[32] Characterized by high incidence and disability rates, these diseases not only severely impact patients' quality of life but also impose a substantial socioeconomic burden, emerging as a global public health issue.[33] In recent years, paeonol, leveraging its favorable pharmacological effects, has demonstrated broad application prospects in the treatment of respiratory diseases, potentially offering patients more effective therapeutic options.

Therapeutic Effect and Mechanism of Paeonol on Asthma

Asthma is a common chronic respiratory disease characterized primarily by airway hyperresponsiveness, inflammatory cell infiltration, and airway remodeling.[34] These pathological changes lead to recurrent symptoms such as wheezing, shortness of breath, chest tightness, and coughing, significantly affecting quality of life.[35] The pathogenesis of asthma is complex, involving various inflammatory cells and mediators, which lead to airway inflammation and hyperresponsiveness, subsequently causing airway narrowing and breathing difficulties.[36] [37] Natural medicines offer certain advantages in treating asthma.[38] Recent studies have elucidated the mechanism of paeonol's action against asthma. Paeonol can significantly ameliorate symptoms, reduce lung tissue inflammatory cell infiltration, and collagen deposition in ovalbumin-induced asthmatic mice. It markedly increases interleukin-4 (IL-4) levels while decreasing the expression of interferon-γ (IFN-γ) and macrophage inflammatory protein-1β. This mechanism is related to the regulation of T helper type 1 (Th1)/T helper type 2 (Th2) cell and cytokine balance.[39] Another study found that paeonol corrects the Th1/Th2 immune imbalance in allergic asthma by increasing IFN-γ levels, inhibiting the secretion of Th2-type cytokines, and reducing serum total immunoglobulin E (IgE) levels, thereby suppressing ovalbumin-induced airway hyperresponsiveness and inflammation.[40] These studies indicate that paeonol holds significant potential in alleviating airway inflammation, modulating immune responses, and protecting lung tissue, providing new insights for the treatment of bronchial asthma.

Therapeutic Effect and Mechanism of Paeonol on Pulmonary Fibrosis

Pulmonary interstitial fibrosis (or idiopathic pulmonary fibrosis, IPF) is a chronic, progressive fibrosing interstitial lung disease of unknown cause, characterized by its idiopathic nature, chronic progression, and poor prognosis.[41] Its pathological features include destruction of the alveolar structure, fibroblast proliferation, and lung tissue fibrosis, leading to lung scarring and loss of normal elasticity and function.[42] In the pathological progression of pulmonary fibrosis, the irreversible remodeling of the lung parenchymal structure makes prevention and early intervention particularly important.[43] An in vivo experiment confirmed that paeonol prevents bleomycin-induced pulmonary fibrosis in mice by inhibiting the mitogen-activated protein kinase (MAPK)/mothers against decapentaplegic homolog 3 (Smad3) pathway.[44] While investigating the therapeutic effects of paeonol and its derivatives on IPF, Zhang et al[45] found that paeonol and its derivatives significantly inhibited the expression of collagen I and α-smooth muscle actin in the lung tissue of bleomycin-induced pulmonary fibrosis mice, modulated the production of senescence-associated secretory phenotype factors, and suppressed fibroblast activity. These findings suggest that paeonol and its derivatives hold promise for alleviating the clinical symptoms of IPF. Paeonol demonstrates certain effects in inhibiting the progression of lung tissue fibrosis, regulating inflammatory responses, and maintaining the structural integrity of lung tissue. Furthermore, research on the biological activity of paeonol derivatives provides new directions for IPF treatment strategies.

Therapeutic Effect and Mechanism of Paeonol on Chronic Obstructive Pulmonary Disease

COPD is a common chronic respiratory disease characterized by persistent airflow obstruction, exhibiting high global morbidity and mortality rates that impose a substantial burden on patients' quality of life and health care resources.[46] The pathological basis of COPD primarily involves chronic inflammation of the airways and lungs, leading to airway narrowing, airflow limitation, and decreased lung function.[47] Combinations of natural compounds can compensate for the shortcomings of single drugs, and their combined application can produce stronger synergistic effects.[48] One study found that paeonol combined with four natural product components—ginsenoside Rh1, icariin, astragaloside IV, and nobiletin—inhibited mucus hypersecretion in COPD rats via the miR-146a-5p/epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway.[49] Moreover, network pharmacology combined with a rat model elucidated that the same drug combination has anti-inflammatory effects against COPD.[50] Preliminary research found that the combination of paeonol and nobiletin effectively inhibited mucus hypersecretion in COPD rats.[51] Additionally, Xu et al[52] discovered that the combination of paeonol with the aforementioned four components could modulate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in COPD rats to ameliorate oxidative stress and protect the lung blood–air barrier. These research results indicate that paeonol holds significant potential in COPD treatment, especially when combined with other drugs, as it can exert synergistic effects through multiple mechanisms. This combination strategy not only enhances therapeutic efficacy but also more comprehensively improves the pathological state of COPD through multitarget mechanisms of action. Therefore, the combined application of paeonol with natural product components may represent an effective treatment strategy for COPD.

Therapeutic Effect and Mechanism of Paeonol on Lung Cancer

Lung cancer, a malignant tumor with high incidence and mortality rates, has become a major global public health challenge.[53] Although advances in diagnostic techniques and treatment methods have achieved certain results, patient prognosis remains poor, primarily due to its complex pathogenesis. These mechanisms include gene mutations, epigenetic alterations, chronic inflammation, and immune escape, which act synergistically to drive abnormal proliferation, invasion, and metastasis of tumor cells, thereby significantly reducing patient survival rates and quality of life.[54] Consequently, inhibiting the proliferation and migration processes of tumor cells has been proven to be a key strategy in lung cancer treatment. Using a new comprehensive pharmacology model, Cai et al[55] found that paeonol significantly inhibited the proliferative activity of A549 cells and induced their apoptosis. Simultaneously, paeonol significantly inhibited the viability, migration, invasion, and TGF-β1-induced epithelial–mesenchymal transition of lung cancer cells in a dose-dependent manner, and suppressed the proliferation and metastasis of human lung cancer cells by regulating the miR-126-5p/zinc finger E-box binding homeobox 2 (ZEB2) signaling axis, suggesting paeonol's potential as a candidate drug for lung cancer treatment.[56] Zhang et al[57] found that paeonol significantly inhibited the growth of lung adenocarcinoma xenograft tumors in nude mice; in vitro experiments showed that paeonol effectively inhibited the migration and invasion of A549 cancer cells, demonstrating good potential for inhibiting lung cancer progression. Furthermore, paeonol significantly inhibited tumor lung metastasis in a tumor xenograft mouse model.[58] Thus, paeonol, by inhibiting multiple signaling pathways, suppresses the migration and invasion capabilities of lung cancer cells, enhances the body's immune surveillance against tumors, and achieves the effect of delaying tumor progression.

Therapeutic Effects and Mechanisms of Paeonol on Other Respiratory Diseases

Paeonol also demonstrates significant therapeutic effects on other respiratory diseases, showing broad potential for clinical application. For instance, one research team developed a microneedle patch loaded with dexamethasone and paeonol. Intranasal administration enabled precise drug delivery to the nasal mucosa, and its sustained-release effect significantly improved symptoms of allergic rhinitis, outperforming double the dose of dexamethasone alone.[59] Notably, another study found that inhaling a paeonol-loaded cyclodextrin metal-organic framework (PAE-CDQ-MOF) dry powder formulation significantly reduced plasma inflammatory factor levels, improved lung histopathology, and markedly ameliorated acute lung injury.[60] Furthermore, paeonol can enhance the antibacterial effect of colistin by targeting membrane phospholipids, effectively combating gram-negative bacteria such as Klebsiella pneumoniae, thus providing a new strategy to address antibiotic resistance issues.[61] [62]

Summary and Prospects

Mechanisms of Paeonol in Treating Respiratory Diseases

In respiratory disease research, paeonol exhibits multiple beneficial pharmacological effects. Studies show it can inhibit inflammatory responses, reduce proinflammatory cytokine levels, alleviate oxidative stress, and improve lung tissue damage, thereby exerting protective effects against respiratory diseases like acute lung injury, COPD, and asthma. Its mechanisms primarily include, in terms of anti-inflammatory effects, paeonol inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and reduces levels of Th2 cytokines (e.g., IL-4) and IFN-γ, thereby alleviating airway inflammation. Regarding antioxidant effects, it activates the Nrf2 pathway and upregulates antioxidant enzyme activity, protecting lung tissue from oxidative stress damage. In immunomodulation, paeonol regulates the Th1/Th2 balance, reduces IgE and histamine levels, enhances the expression of anti-inflammatory cytokines like IL-10, and inhibits the activation of inflammation-related pathways such as p38/ERK/MAPK. For pulmonary fibrosis, it inhibits the TGF-β/Smad pathway and reduces collagen deposition, thereby mitigating fibrotic lesions. In summary, based on multitarget regulation and synergistic effects, paeonol demonstrates multiple actions, including anti-inflammatory, antioxidant, immunomodulatory, and antifibrotic activities, providing important experimental evidence and theoretical support for its potential clinical application in respiratory diseases and new drug development.

Current Challenges and Future Prospects in the Application of Paeonol

Although paeonol possesses good biocompatibility and low toxicity, providing a safety guarantee for its clinical application, it still faces the following main limitations: (1) Low oral bioavailability: Poor absorption characteristics necessitate high dosing, which increases treatment costs and may cause side effects. (2) Insufficient drug stability: Susceptibility to light, temperature, and oxidation not only reduces efficacy but may also produce harmful degradation products. (3) Pharmacokinetic defects: A short half-life and the need for frequent administration significantly reduce patient compliance. Pharmacological studies indicate that paeonol shows unique advantages in combination therapy strategies, where synergistic effects not only significantly enhance therapeutic outcomes but also overcome its inherent low bioavailability.[63] In recent years, researchers have applied novel delivery technologies such as nanocarrier encapsulation,[64] [65] [66] Chinese herbal vesicle systems,[67] [68] as well as sustained-release dripping pills and liposomes.[69] [70] [71] These carriers/formulations significantly improve solubility/stability and enable more stable drug release in vivo with delayed metabolism/excretion.

Furthermore, current research on paeonol in respiratory diseases still has shortcomings: (1) Studies on its pharmacological effects mostly focus on single signaling pathways like NF-κB, Nrf2, or TGF-β/Smad, while the interaction mechanisms within its multidimensional molecular network are not fully elucidated. (2) Current research in the field of respiratory diseases mostly remains at the cellular and animal levels, with relatively insufficient preclinical and clinical translational studies. Its efficacy and safety in real disease courses and complex pathological environments still require further validation. (3) As an active component of Chinese herbs, the combined application of paeonol with other TCM monomers or modern drugs warrants in-depth exploration. These factors collectively limit its widespread clinical application. This research status restricts our comprehensive understanding and in-depth evaluation of its therapeutic potential.

Therefore, future research should focus on the following directions: (1) Utilize pathway-specific agonists/inhibitors, gene knockout, or silencing to clarify the multipathway mechanisms of paeonol in regulating inflammation, immunity, and fibrosis; (2) integrate multiomics technologies and network pharmacology methods to systematically reveal its multitarget regulatory characteristics; (3) conduct systematic preclinical safety and pharmacokinetic studies, and design randomized controlled trials to verify its efficacy and safety in diseases such as asthma, COPD, and pulmonary fibrosis, promoting translation from experimental research to clinical application; (4) evaluate the synergistic effects of paeonol with corticosteroids, antioxidants, or other TCM components to enhance efficacy, reduce drug resistance and side effects, reflecting the advantages of integrated traditional and Western medicine. As a multieffective natural active component, paeonol shows significant application prospects in the field of respiratory disease treatment, and its further development is expected to provide new options for clinical therapy.

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Yuwei Song: Writing—original draft, and investigation. Xixi Wang: Investigation. Bofei Yang: Investigation. Yanqin Qin: Conceptualization, writing—review and editing, and funding acquisition. Liu Yang: Writing—review and editing.

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Publication History

Received: 02 June 2025

Accepted: 24 July 2025

Article published online:
30 December 2025