Lung cancer is the leading cause of cancer-related mortality globally with an estimated 80,000 deaths annually. The mortality from lung cancer is increasing as the population grows and ages (Kocarnik et al., 2022; Fan et al., 2023; Sun et al., 2023; Sung et al., 2021). The incidence and mortality rates are higher in developing countries than in developed countries, exacerbating global disease burden and economic strain (Apple et al., 2023).

Normal lung cells become malignant due to genetic mutations induced by several factors, such as environmental and genetic factors. These mutations occur in genes that regulate cell cycle, DNA repair, and angiogenesis and favor cell growth and survival, resulting in abnormal cell growth and division, unlimited proliferation and spreading of cells (by overriding the normal cell cycle regulation and evading programmed cell death), and tumor formation (Long et al., 2019; Baykara et al., 2015). The transformation from a normal to malignant phenotype involves key alterations, such as inactivation of tumor suppressor genes, activation of proto-oncogenes, dysregulation of apoptosis and telomerase control, sustained angiogenesis, and tissue invasion (Breuer et al., 2005). Fortunately, the occurrence and development of lung cancer is a multistep process, early detection of cancer at the pre-invasive stage may provide an opportunity to inhibit or slowdown the progression of malignant disease, ultimately improving the prognosis in patients (Lantuéjoul et al., 2009; Mascaux, 2008).

The World Health Organization Classification specifies lung cancer precancerous lesions as squamous epithelial atypia and carcinoma in situ, atypical adenomatous hyperplasia, and infiltrative idiopathic pulmonary neuroendocrine cell hyperplasia, which are the early warning signals for the development of lung cancer (Kerr, 2001). Although only 15%–20% of idiopathic pulmonary fibrosis (IPF) cases will progress to lung cancer (Yao et al., 2025), pulmonary diseases such as pneumonia, lung injury, PF, tuberculosis, and COPD are considered risk factors for lung cancer (Li C. et al., 2022; Bhat et al., 2022; Wang L. et al., 2023). The “inflammation-fibrosis-cancer” cascade is not an inevitable pathway, but it does create a favorable environment for tumor development (Feng et al., 2025). In other words, people with pulmonary diseases are at an increased risk of developing lung cancer (Brenner et al., 2012; Brenner et al., 2011).

Pneumonia is mainly treated with antibiotics to eliminate microorganisms. PF has no specific drug, and slowing down the progression of the disease to alleviate the symptoms is the main goal of treatment. The treatment for tuberculosis includes the long-term use of anti-tuberculosis drugs (Khan et al., 2021; Nguyen et al., 2022; Min et al., 2022). COPD is treated with inhaled medications (e.g., bronchodilators and steroids) to ameliorate symptoms, and smoking cessation along with a pulmonary rehabilitation program are recommended to improve lung function (Gupta et al., 2019). Common treatment options for lung cancer include surgical resection, radiotherapy, chemotherapy, targeted therapy, and immunotherapy (Sowa et al., 2017). Collectively, these treatment approaches focus on eliminating infection, immunomodulation, mechanical ventilation, and removal of malignant tissue (surgical interventions). Unquestionably, innovative drugs which can treat lung diseases and inhibit their dynamic development progression to lung cancer are attractive.

Universally acknowledged that artemisinin and its derivatives are the most effective drugs for treating drug-resistant malaria and have a fast-acting and low-toxicity profile. Artemisinin is derived from the plant Artemisia annua L., and its common derivatives include artesunate, dihydroartemisinin, artemether (Posadino et al., 2023; Tang et al., 2023). Evidence is mounting that artemisinin and its derivatives can reduce the disease burden of lung cancer and inhibit the progression of lung diseases to lung cancer. Here, we focused on the multistep pathogenesis of lung cancer, discussed the progression from pneumonia to lung cancer, and investigated the regulatory effect of artemisinin and its derivatives on each step of cancer progression. In addition, toxic side effects of drugs and delivery routes of artemisinin and its derivatives were reviewed.

The lungs are the central organs in the human respiratory system, carrying several important functions, such as respiratory regulation, immune function, and pulmonary circulation (Schneider et al., 2021). The success or failure of pulmonary defense mechanisms determines the emergence of clinical diseases. Pulmonary defense is dependent on the immune and nervous systems. Immune defense is the ability of cells (such as neutrophils and macrophages) and molecules in the lungs to clear pathogens from the alveoli and prevent them from entering the bloodstream (Hiroki et al., 2021). Neurological defenses include aerodynamic filtration, ciliary motility, and other forces that detect external threats through sensory neurons and drive the movement of respiratory fluids (Green et al., 1977). The disruption of these defense mechanisms by various factors leads to lung diseases, which can increase the risk of lung cancer (Shehata et al., 2023; Zou et al., 2022; Cha et al., 2023; Hamada et al., 2023; Hu et al., 2021; Lu et al., 2022; Zhu et al., 2020). It is evident that multiple lung diseases are interconnected, and the evolving transition from lung injury to lung cancer is a dynamic development process.

Pneumonia is a lung infection caused by bacteria, viruses, or fungi (Michelet et al., 2021). Microbial pathogens enter the respiratory tract, triggering an inflammatory response that damages lung tissue (Tian et al., 2023). In addition, inflammatory response increases the permeability of the alveolar walls, leading to the leakage of fluid and cells from the alveoli and the formation of parenchymal lung lesions (Holloway et al., 2018). The uncontrolled inflammatory responses may aggravate lung infections and cause serious lung damage (Garg et al., 2021). Hence, lung injury is a more serious disorder compared with pneumonia. In addition to infection and inflammation, lung injury is usually caused by trauma and several other factors (Habet et al., 2023). The inflammatory response is further exacerbated in lung injury, leading to diffuse damage to alveolar epithelial cells, decrease in lung surface-active substances, destruction of the alveolar walls, increased permeability of the basolateral membranes, accumulation of intra-alveolar fluid, accumulation of polymorphonuclear leukocytes, parenchymal cell damage, and interstitial edema (Meng et al., 2018). Ultimately, continued damage to the lung epithelium due to uncontrolled inflammation leads to abnormal lung tissue repair. Moreover, inflammatory response activates fibroblasts, leading to increased collagen synthesis. This collagen is deposited in the lung tissue to form fibrotic lesions (Ammar et al., 2019; Wei et al., 2023). Accordingly, we refer to pneumonia and lung injury as the phase Ⅰ of dynamic development processes of lung diseases to lung cancer.

PF involves fibrotic tissue proliferation in the lungs. Its pathologic progression involves complex interactions between epithelial cells, mesenchymal stem cells, fibroblasts, immune cells, and endothelial cells (Zhang and Wang, 2023). Fibrosis, overgrowth, sclerosis, and scarring of various tissues are attributed to the expansion of activated mesenchymal stromal cells (myofibroblasts), leading to excessive deposition of extracellular matrix components in basement membranes and interstitial tissues (Makena et al., 2023). Gradual loss of elasticity and function of lung tissue occurs as the fibrous tissue proliferates and deposits, leading to dyspnea and other clinical symptoms (Marts et al., 2019). Molecular and cellular processes, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, altered expression of growth factors, and oxidative stress, link PF to lung cancer and increase the risk of cancer development by 7%–20% (Ballester et al., 2019).

In addition, lung damage and fibrosis are frequently observed in tuberculosis (Ravimohan et al., 2018). It is a chronic infectious disease caused by Mycobacterium tuberculosis, which enters the lungs and triggers an immune response that results in the formation of tuberculous nodules (Huang et al., 2022). These nodules contain macrophages and lymphocytes that control the spread of bacilli (Fallahi-Sichani et al., 2010). However, these nodules develop into foci if the immune response fails to control the infection (Khan et al., 2019). Tuberculosis is a known risk factor for lung cancer because chronic inflammation and fibrosis may induce genetic mutations and DNA damage, leading to lung cancer (Schabath and Cote, 2019; Hwang et al., 2022).

COPD is a chronic inflammatory disease characterized by airway obstruction, alveolar destruction, and reduced lung function. The disease is projected to become the third leading cause of death worldwide by 2030 (Li et al., 2023). Patients with COPD have a 4–6 times higher risk of lung cancer compared with non-COPD patients (Shih et al., 2021). Smoking is the most common cause of COPD and lung cancer, and approximately 85%–90% of cases are associated with exposure to tobacco smoke (Czarnecka-Chrebelska et al., 2023). Harmful substances in tobacco smoke trigger an inflammatory response in the airways, leading to increased chemotaxis of bronchial mucosal cuprocytes and mucus secretion. The subsequent release of inflammatory cells can damage lung tissue leading to PF, destruction of the alveolar walls, and reduced lung function (Cheng et al., 2015). In addition, inflammation can increase DNA damage and mutations, leading to tumor proliferation, anti-apoptotic effects, angiogenesis, invasion, and metastasis (Zhou et al., 2023). In the continuous progression of pneumonia and lung injury, various lung diseases (PF, tuberculosis and COPD) emerge, all of which can directly raise the risk of lung cancer. Thus, we define them as the phase Ⅱ of the dynamic development processes.

Lung cancer is a malignant tumor segregated into two main groups, namely non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), with NSCLC accounting for 80%–85% of the diagnosed cases (Guo et al., 2021). Inflammation, immunity, oxidative stress, cell proliferation, apoptosis, and mitochondrial dysfunction play important roles in the development and progression of lung cancer (Liu J. et al., 2023; Wang et al., 2024a; Pang et al., 2024). Inflammation can damage lung tissue and induce DNA damage in lung cells, mitochondrial DNA damage leads to the dysregulation of mitochondrial quality control, which lays the foundation for the malignant transformation from stage II (such as pulmonary fibrosis) to stage III (lung cancer), thereby increasing the risk of lung cancer (Taucher et al., 2022). Under normal circumstances, immune cells can inhibit the development of lung cancer by recognizing and removing abnormal lung cells. In contrast, tumor cells often evade immune surveillance through various “immune escape” mechanisms to avoid recognition and elimination, thereby promoting tumor growth and metastasis (Rui et al., 2023). In addition, oxidative stress, mitochondrial quality control and mechanisms involved in cell proliferation, apoptosis, and cell cycle regulation are closely related to the occurrence and development of lung cancer (Deng et al., 2013; Larson-Casey et al., 2020; Chang et al., 2023). Lung cancer represents the final stage of the development processes and is classified as phase Ⅲ.

Overall, prior lung disease increases the risk of lung cancer (Brenner et al., 2012; Brenner et al., 2011). Lung cancer is a multistep and multidimensional process, pneumonia and lung injury are inflammatory diseases that increase the risk of lung cancer, PF, tuberculosis, and COPD are precursor diseases that further promote the development of lung cancer (Figure 1). Compared with treating cancer, the approach of prevent is more feasible and practical, identifying risk factors and implementing prevention strategies are key to reduce the global burden of lung cancer (Garrison et al., 2021).

Artemisinin, a sesquiterpene lactone, is a first-line drug for the treatment of malaria. It was first extracted from A. annua L. by Tu Youyou and colleagues in 1972 (Fikadu and Ashenafi, 2023), and is a colourless crystal with the molecular formula C₁₅H₂₂O₅. The metabolic pathway of artemisinin primarily involves hepatic and intestinal metabolism. In hepatic metabolism, the CYP450 enzymes convert artemisinin into metabolites for easier excretion through oxidation, reduction, and hydrolysis processes (Asimus et al., 2007). Furthermore, specific bacteria in the intestinal microbiota can metabolize artemisinin via hydroxylation and sulphonation, these metabolites then pass into the bloodstream through the liver and kidneys before being eliminated from the body. Artemisinin has poor water and fat solubility, poor stability, and low oral bioavailability, limiting its clinical applications (Yu et al., 2012). Fortunately, several artemisinin derivatives, including dihydroartemisinin, artesunate and artemether have been synthesized (Figure 2). These derivatives are structurally slightly different but have similar therapeutic effects, anti-parasitic for instance, anti-tumor, anti-inflammatory, anti-viral, and dermatological treatments (Huang et al., 2023). Particularly, they have higher bioavailability and longer half-lives than artemisinin (Kol et al., 2022).

Artemisinin’s biological activity is linked to its peroxy bridge, derivatives are created by modifying its structure while retaining the peroxy bridge. Currently, all derivatives modify the C-9 and C-10 positions, with C-10 being the most common. Dihydroartemisinin, the simplest derivative, is obtained by reducing the carbonyl group at the C-10 position to a hydroxyl group, resulting in a molecular formula of C₁₅H₂₄O₅. Studies show it has a longer half-life and higher bioavailability, but poor aqueous solubility (Zang et al., 2014; Morris et al., 2011). Artesunate, with a molecular formula of C₁₉O₈H₂₈, is derived from dihydroartemisinin and succinic anhydride. It exhibits mild acidity, can penetrate biofilms, and possesses high efficacy, low toxicity, and high tolerability (Michener et al., 2023; Lin et al., 2022). Artemether is obtained by replacing the hydrogen atom on the hydroxyl group at the C-10 position with a hydrocarbon group. Compared to other derivatives, artemisinin ether derivatives are more fat-soluble but less water-soluble, with low bioavailability (de Vries and Dien, 1996).

Artemisinin and their derivatives have a wide range of pharmacologic effects, including anti-inflammatory, antioxidant, antifibrotic, and antitumor effects, in addition to their broad-spectrum antimalarial activity. These compounds have been investigated for the treatment of rheumatoid arthritis, renal injuries, gastric cancer, lung cancer, and other diseases (Yang et al., 2023). Although these studies are currently in the basic research phase, some clinical trials have shown promising results. In this review, we focused on the multistep pathogenesis of lung cancer and investigated the regulatory effect of artemisinin and its derivatives on each step of cancer progression.

PubMed and China Knowledge Network were searched from the start date to October 2023. Search terms included “artemisinin”, “artesunate”, “dihydroartemisinin”, “artemether”, “artemisinin dimer”, “sodium artesunate”, “lung, pulmonary fibrosis”, “pulmonary nodules”, “tuberculosis”, “lung cancer”, “pneumonia”, “lung injury”, “chronic obstructive pulmonary disease”. The research papers published on the use of artemisinin and its derivatives for the treatment of lung cancer and diseases that increase the risk of cancer were included in the analysis. Finally, we studied drugs including artemisinin, dihydroartemisinin, artesunate, and artemether, the diseases including pneumonia, lung injury, lung fibrosis, and lung cancer, the details of including literature were listed at Tables 1–3. The types of research studies were animal experiments, cellular experiments, or clinical trials.

High mobility group box 1 protein (HMGB1) is an upstream signaling protein that regulates inflammation and activates TLR4. TLRs are a family of innate immune recognition receptors that activate myeloid differentiation factor 88 and NF-κB (Yuan et al., 2023), NF-κB is a transcription factor that plays a key role in cellular inflammatory and immune responses (Yuan J. et al., 2020). Artesunate and dihydroartemisinin may exert immunomodulatory effects by regulating HMGB1 expression, inhibiting TLR4/NF-κB activation, decreasing TNF-α, IL-6, IL-1β, iNOS, and Cox-2 expression, and attenuating inflammation caused by pneumonia, lung injury, lung fibrosis, and lung cancer (Deng et al., 2018; Han et al., 2023).

TGF-β1 is a cytokine that regulates cell growth and differentiation and promotes the transformation of lung fibroblasts into myofibroblasts, which then synthesize and release high concentrations of matrix proteins components into the extracellular matrix, leading to lung fibrosis. The Smad proteins are specific intracellular signaling molecules of the TGF family. TGF-β1 signaling induces the phosphorylation of JAK2, which activates the JAK2/STAT3 signaling pathway to promote inflammatory response and fibrosis. Dihydroartemisinin reduces the expression of TGF-β1 and, Smad2/3, inhibits the activation of JAK2/STAT3, attenuates the expression of inflammatory factors (IL-6, TNFα, and chemokine ligand 3), and reduces the infiltration of inflammatory cells (You et al., 2022; Zheng et al., 2019). In addition, dihydroartemisinin can inhibit PD-L1 expression, promote T-cell growth, and increase the killing capacity of T cells. Ultimately, dihydroartemisinin prevents tumor immune escape by inhibiting the TGF-β, PI3K/Akt, and STAT3 signaling pathways to promote tumor eradication (Zhang E. et al., 2020; Zhang H. et al., 2020).

Nrf2 is an important initiator of the oxidative stress pathway. The activated Nrf2 translocates to the nucleus and regulates the transcription of antioxidant proteins such as HO-1. ROS are mainly generated by redox reactions and have a dual role in tumor cells. SOD, GSH, and MDA are the common biomarkers of oxidative stress. Artesunate and dihydroartemisinin reduced oxidative stress in lung tissues in a dose-dependent manner by modulating the Keap1/Nrf2 signaling pathway. Notably, Nrf2 translocates to the nucleus in ROS-sensitive cells, increases the antioxidant HO-1 levels, decreases the MDA levels, and increases the SOD and GSH activities (Xie et al., 2023; Huang et al., 2019; Zhao et al., 2017; Xin et al., 1998). In addition, artesunate can enhance the antioxidant defense system and prevent oxidative damage in the lungs by inhibiting the PI3K and p42/22 MAPK signaling pathways, decreasing the levels of oxidative biomarkers (8-IPS, 8-OHdG, and 3-NT), promoting anti-hydrogen peroxide dismutase activity in lung tissues, and decreasing the expression of NADPH (Ng et al., 2014).

The combination of artesunate and dihydroartemisinin downregulates PERK, ATF4, and CHOP, reduces Fe²⁺ concentration, attenuates iron-induced cell death, and ameliorates lung injury (Xu et al., 2024). Dihydroartemisinin decreases GPX4, FTH1, and NCOA4 expression and reduces Fe²⁺ levels by inhibiting the PRIM2/SLC7A11 axis (YU, 2021; Lai et al., 2023; Yuan B. et al., 2020).

Artesunate may inhibit the proliferation of lung cancer cells, downregulate the expression of anti-apoptotic molecules Bcl-2 and survivin, upregulate the expression of pro-apoptotic molecules P53 and Bax, and increase the activity of caspases and apoptosis rate through the PPAR-γ/TGF-β1/Smad2/3, AKT/Survivin, P38/JNK/ERK, and MAPK pathways (Pan et al., 2021; Wang et al., 2014; Zhang, 2010; Li W. et al., 2021; Xin et al., 1998). This compound increases the expression of E-calmodulin, decreases the levels of N-calmodulin, vimentin, and FN1, inhibits EMT, and decreases the migratory ability of NSCLC cells (Wang et al., 2020). Moreover, artesunate induces the G2/M cell cycle blockade in HFL-I and H460 cells and blocks the cell cycle in the G0/G1 phase in H1975 and LLC cells. Notably, the combination of artesunate with cisplatin enhanced cell cycle blockade in the G2/M phase (Zhang, 2010; Cao et al., 2022; Li W. et al., 2021).

Dihydroartemisinin inhibited the proliferation of A549 and HCC827 cells in a dose-dependent manner. In addition, dihydroartemisinin treatment significantly downregulated Ki-67, PCNA, PARP, and Bcl-2 expressions, upregulated cysteine 3 and Bax expressions, and increased the percentage of TUNEL-positive cells. Moreover, dihydroartemisinin may decrease the expression levels of the key G0/G1 regulators, CDK2/4, and cyclin E1 through the mTOR/HIF-1α signaling, thereby inducing A549 cell cycle blockade and alleviating gefitinib resistance (Hu et al., 2023; Lai et al., 2023; Li Y. et al., 2021). Overall, artemisinin and dihydroartemisinin regulate multiple pathways, such as TLR4/NF-κB, Keap1/Nrf2, mTOR/HIF-1α, PI3K/Akt, AKT/mTOR, JAK2/STAT3, and MAPK, by modulating cellular processes including inflammation, immunity, oxidative stress, ferroptosis, apoptosis, cell proliferation, and cell cycle arrest. Thereby, they ameliorate lung cancer precursor lesions such as pneumonia, lung injury, PF, and COPD, consequently reducing the risk of cancer. In addition, artemisinin and its derivatives regulate several cellular processes, including glycolysis, angiogenesis, and cellular autophagy, even when lung injury, PF, and COPD are not involved. These research directions may be explored in the future.

This review highlighted the fact that the dynamic development processes of lung diseases to lung cancer, elaborated on the pathologic states of pre-lung cancer diseases and the mechanisms by which they progress to lung cancer. In addition, we discussed the therapeutic effect of artemisinin and its derivatives on different diseases that increase the risk of lung cancer and explored the common regulatory mechanisms. Finally, we summarized the development of targeted drug delivery systems for artemisinin and its derivatives.

Pneumonia, lung injury, PF, tuberculosis, and COPD increase the risk of lung cancer to varying degrees. Artemisinin and its derivatives can reduce DNA damage, oxidative stress, and inflammation, inhibit cell proliferation, promote apoptosis, and regulate the cell cycle through multiple pathways, such as the TLR/NF-κB, Keap1/Nrf2, and PI3K/Akt signaling pathways, thereby exerting a therapeutic effect on lung cancer and pre-lung cancer diseases. Moreover, these compounds can regulate glycolysis, inhibit angiogenesis, increase cellular autophagy, and repair lung injury. Nanoscale delivery systems, such as polymer-drug nanoparticles, micelles, and liposomes, are being developed to increase their bioavailability and improve drug stability, which will improve the therapeutic efficacy.

Artemisinin and its derivatives can be used as both anti-lung cancer and lung protective agents in clinical application. Current research focuses on artesunate and dihydroartemisinin. However, clinical trials to verify their efficacy are still lacking. Future studies should focus on more artemisinin derivatives, and clinical trials should be conducted to validate the efficacy of artemisinin-based approaches for the prevention and treatment of lung cancer.