Талидомид взаимодействует с воспалением в идиопатическом фиброзе легких.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic fibrotic scarring of lung tissues, leading to a deterioration of lung function and respiratory failure. Disease progression ultimately leads to death within a few years. IPF is presumably caused by multiple causes such as smoking, drugs (E.g., bleomycin), inhalation of metallic particles, wood dust or silica, and exaggerated immune responses (Barratt et al. 2018 ). Environmental factors and epigenetic mechanisms such as DNA-methylation and histone modifications are major contributors to disease progression (Velagacherla et al. 2022 ). IPF is an abnormal wound healing process where micro-injuries to the alveolar epithelium do not heal appropriately (Richeldi et al. 2017 ). IPF is a chronic fibrotic disease and symptomatically overlaps with cryptogenic fibrosing alveolitis. In IPF, an altered extracellular matrix (ECM) replaces the healthy lung tissue, damaging alveolar integrity, which is reflected by decreased lung compliance, abnormal gas exchange, respiratory failure, and eventually, death. IPF histopathology reflects interstitial pneumonia with fibroblast foci as hallmark lesions (Martinez et al. 2017 ). IPF is caused by sustained micro-injuries to the alveolar epithelial tissue, combined with abnormal healing processes leading to the depletion of the basement membrane between the alveolar epithelium and the capillaries (Wuyts et al. 2020 ). IPF is most prevalent in South Korea, Canada, Poland, the United States, and Italy (Maher et al. 2021 ). The COVID-19 pandemic could have augmented the growing incidences of IPF (Tanni et al. 2021 ). The pathogenesis of post-COVID-19 pulmonary fibrosis involves TGF-β1, which facilitates the release of extracellular proteins, fibroblast proliferation, fibroblast migration and, myofibroblast conversion (Al-kuraishy et al. 2022 ). Furthermore, genetic susceptibility for IPF and COVID-19 seem to be similar, as confirmed by the fibrotic plasma biomarkers such as thrombospondin 2 (TSP2), glial-derived factor 15 (GDF15), insulin-like growth factor binding protein 7 (IGFBP7), and procollagen type III (PROC3) (Ackermann et al. 2022 ). Currently, the therapeutic management of IPF consists of symptomatic treatment and extensive palliative care, because nintedanib and pirfenidone are the only two drugs approved for the indication of IPF (Mudawi et al. 2021 ). In this review, we propose that thalidomide can mitigate inflammation in IPF, and can be repurposed either as monotherapy or in combination with nintedanib and pirfenidone.

Thalidomide is a synthetic glutamic acid derivative α-(N-phthalimido)-glutarimide (Fig. 1 ), originally designed as a non-addictive and non-barbiturate sedative. (Kim and Scialli 2011 ). Thalidomide has one asymmetric carbon in the glutarimide ring, which acts as a chiral centre and gives rise to two enantiomers, R(+) and S(−). These enantiomers are capable of interconverting under appropriate biological conditions (Vargesson 2015 ). Being hailed as a ‘wonder drug’ at the time of its introduction, thalidomide was used as a quick and effective anti-emetic to treat morning sickness in pregnant women (Sharma and Kwatra 2016 ). It appeared to be non-toxic in rodent models. Hence, an LD 50 value was not established, and it was assumed to be safe for humans (Cooper et al. 2010 ). Thalidomide received a lot of attention for being inexpensive and easily available without prescription. Thalidomide was widely marketed in European countries, Australia and Japan. It was first marketed in West Germany in 1957 under the trade name Contergan VR by Chemie Grunenthal, a German pharmaceutical company, and was later approved and distributed in 46 countries around the world under various brand names (Kumar et al. 2012 ). In 1960, around 14.6 tonnes of thalidomide were believed to be sold in Germany alone, making it the best-selling sedative in the market (Rehman et al. 2011 ). However, what came next was one of the most catastrophic man-made clinical disasters in history. There were multiple cases of limb malformations, birth defects and even death of thousands of babies born to mothers who consumed thalidomide during their early trimester of pregnancy (Kim and Scialli 2011 ). Thalidomide was withdrawn from the market in September 1961 when two scientists, McBride in Australia and Lenz in Germany, confirmed the association of thalidomide with congenital disabilities such as limb deformities, congenital cardiac, renal and other organ malformations (Mellin and Katzenstein 1962 ). Although thalidomide was swiftly withdrawn from the market, more than 10,000 infants suffered from congenital defects, with the survivors still suffering even today (Newbronner et al. 2019 ). However, the drug thalidomide is still an interesting molecule in drug discovery because of its anti-inflammatory and immunomodulatory properties and is now classified along with immunomodulatory imide drugs (IMiDs) such as lenalidomide, pomalidomide, apremilast, 3,6′-dithiopomalidomide, 3,6′-dithiothalidomide, N-adamantyl phthalimidine, and dithiophthalimide (Furihata et al. 2020 ). Some of these IMiDs are proposed for repurposing in neuropsychiatric and neurodegenerative disorders (Jung et al. 2021 ). Fig. 1 Structure of thalidomide showing its R( +) and S(-) enantiomers and its actions. The structure of thalidomide has asymmetric carbon (•); Both R( +) and S( −) enantiomers are equally active as they are interconvertible in the body

Therapeutic actions which enabled the re-entry of thalidomide

Due to the teratogenic effects, thalidomide was withdrawn late in November 1961 (Samel et al. 2019 ). However, the journey of thalidomide did not end there. In 1965, when thalidomide was administered as a sedative to patients with leprosy (Sheskin 1965 ), it was observed that along with its sedative action, thalidomide also reduced elevated body temperature, and stimulated the reabsorption of erythema nodosum-like skin lesions in patients with leprosy (Sheskin 1965 ). Thus, it was reintroduced into the market with extreme caution for the treatment of erythema nodosum leprosum, based on its immunomodulatory, anti-angiogenic, and anti-inflammatory actions. In the 1980s, thalidomide was given to patients with classic and definitive rheumatoid arthritis (Gutiérrez-Rodríguez 1984 ). In these patients, the erythrocyte sedimentation rate reportedly returned to normal within a few weeks, pain and joint inflammation disappeared, and the rheumatoid factor titers had significantly decreased (Gutierrez-Rodriguez et al. 1989 ). In 1986, a clinical study was conducted on the effect of thalidomide in 30 male patients suffering from Behçet’s disease, which is characterized by inflammation of the blood vessels in the body (Hamza 1986 ). The results demonstrated that thalidomide could be useful in treating clinical manifestations of Behçet’s disease. The side effects observed included skin rashes and somnolence, and were uncommon (Hamza 1986 ).

Thalidomide also selectively inhibited tumour necrosis factor-alpha (TNF-α) production in lipopolysaccharide-stimulated monocytes (Piura et al. 2013 ). However, there was no change in the levels of granulocytes / macrophage colony-stimulating factor, and cytokines [interleukin-6 (IL-6) and interleukin-1-beta (IL-1β)] produced by the monocytes. This could be due to increased degradation of TNF-α mRNA. This allowed the use of thalidomide in the treatment of severe inflammatory diseases (Majumder et al. 2012 ). Thalidomide has also been used in the treatment of wasting syndrome in HIV-AIDS patients (Reyes-Terán et al. 1996 ). In addition, the anti-TNF-α action of thalidomide was considerably helpful in treating tuberculous meningitis in children (van Toorn et al. 2021 ). An in vivo experiment in rabbits concluded that thalidomide is a potent inhibitor of angiogenesis (D’Amato et al. 1994 ). Among the putative angiogenesis inhibitors tested, thalidomide was the only drug that was effective orally suggesting that thalidomide is a feasible anticancer agent (Zhu et al. 2021 ). Thalidomide has also shown promising activity against various solid tumours such as breast cancer, renal cancer, Kaposi’s sarcoma, liver cancer, lung cancer, and several glioblastomas (Amare et al. 2021 ). US FDA authorized thalidomide for the treatment of erythema nodosum leprosum in 1998, and multiple myeloma in 2006 (Rehman et al. 2011 ). Its use in multiple myeloma was attributed to the immunomodulatory and anti-angiogenic activity which downregulates the expression of TNF-α and IL-6 by the stromal cells in the bone marrow, thereby inhibiting the proliferation of multiple myeloma cells (Holstein and McCarthy 2017 ). A recent compilation by Barbarossa et al. listed more than 130 analogues of thalidomide that were tested to treat cancer (Barbarossa et al. 2022 ). Efforts have now been made to strictly regulate the use of thalidomide to prevent potential harm from thalidomide. Several programmes have been developed to manage this. Risk Evaluation and Mitigation Strategies is a programme that controls the prescription of thalidomide (Brandenburg et al. 2017 ). The System for Thalidomide Education and Prescribing Safety (STEPS) is yet another initiative designed to supervise the distribution and use of thalidomide (Khalil et al. 2020 ).

Unfolding the mechanism of action of thalidomide for drug repurposing

Understanding the mechanism of teratogenicity is crucial for safer repurposing of thalidomide and its analogues for therapeutic applications. Soon after the horrifying thalidomide tragedy, research began on the teratogenicity of the drug. In 1979 (Blaschke et al. 1979 ), after thorough research on the thalidomide enantiomers, it was established that the (R)- and (S)- enantiomers possess varying biological characteristics, with the teratogenicity induced only by the (S)-enantiomer. No embryopathy was reported when the (R)- enantiomer was tested in animals (Tokunaga et al. 2018 ). There were several hypotheses proposed to explain the abnormal foetal development caused by thalidomide. One such theory was that thalidomide induces oxidative stress, thereby altering the NF-ĸB activity, causing impaired limb formation and other complications in embryos (Hansen et al. 2002 ). Another theory attributed the teratogenicity to the anti-angiogenic action of thalidomide, suggesting that there is a downregulation of growth factors and aberrant blood vessel formation at the limbs (D’Amato et al. 1994 ). However, these theories failed to elaborate on the targets of thalidomide and how these targets regulate its action (Asatsuma-Okumura et al. 2020 ).

In 2010, a breakthrough study identified that thalidomide binds to a protein called cereblon, linked to a crucial gene for mental retardation (Ito et al. 2010 ). Cereblon was recognized as the primary target for thalidomide. Cereblon is known to bind to another protein called damaged DNA binding protein 1 (DDB1) (Ito et al. 2011 ). Further, the DDB1 and Cul4 (cullin-4) configure an E3-ubiquitin ligase complex called Cullin-RING Ligase-4 (CRL4 CRBN ) (Chang and Keith Stewart 2011 ). This complex plays a vital role in the limb formation and expression of growth factors necessary for limb development (Ito and Handa 2012 ). Thus, it was concluded that the primary targets of thalidomide are (a) cereblon, which interacts directly with thalidomide, and (b) DDB1, which then interacts indirectly by its binding to cereblon (Ito et al. 2010 ). By binding to cereblon, thalidomide interferes with the normal functioning of the ligase complex and causes the degradation of certain neosubstrates, thus altering the expression of genes related to embryonic growth, leading to foetal abnormalities (Fig. 2 ) (Gao et al. 2020 ). Therefore, thalidomide and its analogues are now considered as cereblon-modulating drugs, especially for cancer treatment (Asatsuma-Okumura et al. 2019b ). Further, Ito and Handa ( 2020 ) have explained the old and the current model of thalidomide mechanism of action to induce teratogenicity and its exploration in recent drug development (Ito and Handa 2020 ). Thalidomide downregulates fibroblast growth factor 8 (FGF8), thereby upregulating the apoptotic genes in the limbs (Kawamura et al. 2014 ). Therefore, the FGF8 downregulation could be another molecular mechanism that explains the abnormally short limbs in deformed infants exposed to thalidomide during embryonic development (Asatsuma-Okumura et al. 2019a ). The cereblon protein is found primarily in the brain, particularly the cerebellum. Mutations in the cereblon gene is associated with mental retardation, compromising cognitive processes and memory (Choi et al. 2018 ). Apart from the brain, cereblon is largely present in the kidney, lung, liver, intestines, placenta, and prostate. Further, cereblon engages in the regulation of several other processes, such as the regulation of calcium and chloride channels (Kim et al. 2016 ). Cereblon also acts as a substrate receptor protein in the E3-ubiquitin ligase complex and determines the specificity of the substrate-binding to the complex. Hence, cereblon is pivotal in handling the degradation of many substrates (Liu et al. 2015 ). However, the recent study by Kowalski et al., also says that the cereblon mechanism vary highly between 14 species. Thalidomide does not have teratogenic effect in mice, while limb anomalies are absent in rats. In rabbits and sheep, thalidomide produces teratogenic effects, and the teratogenic characteristics in Rhesus monkeys are similar to that of humans (Kowalski et al. 2021 ). Fig. 2 Mechanism of thalidomide-induced teratogenicity. Thalidomide binds to cereblon (CRBN), which is a part of the E3-ubiquitin ligase complex with the damaged DNA binding protein 1 (DDB1), and cullin-4 (Cul4) forming Cullin-RING Ligase-4 (CRL4CRBN) complex. This leads to an interruption in the normal functioning of cereblon and recruitment of ‘neosubstrates’ such as SALL4 and p63 for degradation, initiating altered gene expression and subsequent limb malformations. Figures are created with created with BioRender.com

Etiopathogenesis and role of cereblon in pulmonary fibrosis

Despite extensive research over the past years, the pathogenesis of IPF remains unclear. Recent advances have linked the disease to inflammation and oxidative stress, which occurs in response to tissue injury. Generally, several endogenous and external factors contribute to tissue injury and damage the alveolar epithelium. Genetic factors such as polymorphisms of the surfactant protein or variations in the mucin 5B gene ( MUC5B/Muc5b ) (Michalski and Schwartz 2020 ), environmental factors such as inhalation of irritant dust particles, microbial infections, lifestyle habits such as cigarette smoking, are some of the attributable factors (Kärkkäinen et al. 2017 ; Denver et al. 2018 ). The aetiology of the most common lung fibrotic condition, IPF, is still not clearly understood. However, the genetic and epigenetic factors equally contribute to the etiopathogenesis of IPF (Velagacherla et al. 2022 ). The telomerase reverse transcriptase ( TERT ) gene is involved in more than 50% of IPF patients (van Batenburg et al. 2020 ). TERT is highly expressed in chronic smokers, which signifies the role of epigenetics (Diaz de Leon et al. 2010 ). What was earlier thought to be chronic inflammation is now being attributed to an aberrant wound healing in genetically susceptible individuals (Daccord and Maher 2016 ). It is now believed that there is dysregulation at any of the three processes: (i) injury (ii) inflammation (iii) repair, along with the overexpressed pro-fibrotic mediators such as TGF-β, and IL-1β. This leads to cellular and molecular modifications that develop fibrosis by the formation of myofibroblasts and deposition of ECM components such as collagen in the tissues (Wilson and Wynn 2009 ; Cinausero et al. 2017 ). Research has established that epigenetic factors and sustained injuries to the alveolar epithelial layer lead to the activation of alveolar epithelial cells (AECs). These activated AECs further engage in the attraction of inflammatory cells and promote fibrogenesis by activating fibroblasts. The fibroblasts differentiate into myofibroblasts and facilitate the process of fibrosis (Magnini et al. 2017 ) (Fig. 3 ). Fig. 3 Etiopathogenesis of pulmonary fibrosis. Repeated tissue injuries cause AECs to undergo apoptosis and re-epithelialization, causing the recruitment of inflammatory cells and profibrogenic mediators, and subsequent ECM accumulation, leading to fibrosis. ECM: Extracellular matrix, EMT: Epithelial mesenchymal transition. Figures are created with created with BioRender.com

Recent research on the implications of cereblon in IPF has opened up a new drug target (Kang et al. 2021 ). Cereblon modulates the energy metabolism by negatively regulating the activation of the AMP-activated protein kinase (AMPK)-signalling pathway (Lee et al. 2011 ). Thus, the role of cereblon-AMPK signalling pathway in IPF can be explored for drug discovery. In recent studies, AMPK activators such as metformin, have shown a protective effect against IPF by preventing the TGF-β/Smad signalling pathway and release of collagen, fibronectin, α-smooth muscle actin (α-SMA), and other fibrogenic factors (Rangarajan et al. 2018 ; Cheng et al. 2021 ; Wu et al. 2022 ). Therefore, activation of AMPK may inhibit the TGF-β-induced fibroblast proliferation (Chen et al. 2022 ). AMPK has also shown an inhibitory action on Forkhead box protein M1 (FOXM1), which is a crucial transcription factor in the process of cell proliferation. FOXM1 is now found to play a role in activating fibroblasts and their proliferation (Gu et al. 2021 ). The activation of AMPK also decreased the endoplasmic reticulum stress and unfolded protein response, both of which are driving factors for the development of fibrosis by inducing tissue injury in the alveolar epithelium (Choi et al. 2016 ; Burman et al. 2018 ). A computational investigation of a well-known AMPK activator DHFO, having structural features that are slightly different from thalidomide was reported to have better CRBN binding affinity than thalidomide (Nayek et al. 2022 ), Thus, the activation of the AMPK signalling pathway is crucial for protecting against IPF.

The overexpression of cereblon would lead to the inactivation of AMPK, and subsequent progression of IPF. Cereblon binds to the α-subunit of AMPK and reduces its overall catalytic activity, which suppresses the activation of AMPK, and worsens IPF (Kang et al. 2021 ). A recent study conducted by Kang et al. in 2021 has provided a strong basis for the association of cereblon in IPF by showing that the collagen and fibronectin were decreased in cereblon gene (CRBN) knockout mice. On the other hand, the TGF-β-induced phosphorylation and activation of Smad proteins, which occurs through CRBN activation, was decreased in the presence of an AMPK activator such as metformin (Kang et al. 2021 ). Moreover, higher expression of cereblon is also related to increased lung injury by oxidative stress, followed by inflammation. This can be subdued by repressing the expression of cereblon, which will downregulate the activation of the NF-ĸB pathway and its downstream mediators in the lungs (Yang et al. 2020 ). Hence, modulation or inhibition of cereblon by thalidomide and its analogues could be a novel approach to treating IPF (as depicted in Fig. 4 ). Fig. 4 Role of cereblon and actions of thalidomide in pulmonary fibrosis. Overexpression of cereblon (CRBN) leads to the downregulation of AMPK, which otherwise inhibits TGF-β-induced fibroblast proliferation, myofibroblast differentiation and epithelial-mesenchymal transition (EMT). Thus, CRBN inhibits the protective actions of AMPK against pulmonary fibrosis. By inhibiting CRBN thalidomide stops the progression of fibrosis. Figures are created with created with BioRender.com

Current treatment options for pulmonary fibrosis

Currently, there are two approved drugs for IPF available in the clinics, namely pirfenidone and nintedanib. They are well tolerated upon long-term treatment without any newer safety alerts (Cameli et al. 2020 ). Due to the poor understanding about pathogenesis of IPF, there have been several therapeutic failures over the past decades. This has left us with minimal treatment options for IPF. The earliest approach was to target the resulting inflammatory response using immunomodulators and anti-inflammatory drugs. Drugs targeting inflammatory and immune responses were recommended in the latest update of clinical practice guidelines on the treatment of IPF (Luppi et al. 2021 ). There are clinical trials conducted on drugs for the treatment of IPF that were later declared potentially harmful (Lota and Wells 2013 ). One such trial was based on the importance of the coagulation cascade in IPF (Kubo et al. 2005 ). The drug warfarin did not show any benefit to patients with progressive IPF, and moreover, warfarin treatment was associated with increased mortality in patients with IPF (Noth et al. 2012 ). Another drug named everolimus, a macrocyclic proliferation signal inhibitor with anti-fibroproliferative activity, was tested for its efficacy in IPF (Malouf et al. 2011 ). This trial involving 89 patients with IPF, (confirmed by surgical lung biopsy) concluded that everolimus was associated with rapid disease progression (Malouf et al. 2011 ). One of the widely used treatments for IPF was a combination of prednisone, azathioprine, and N-acetylcysteine. However, the safety of this drug combination was not established. After a 60 week treatment period and 32 weeks follow-up, this three-drug combination was conclusively implicated with an increased risk of hospitalization and death (Raghu et al. 2012 ). There are quite a few clinical trials of ineffective drugs which made a landmark contribution to IPF patient care. One such clinical trial was on sildenafil, a phosphodiesterase-5 inhibitor. The study on 180 patients treated with sildenafil did not meet its pre-defined significance (Zisman et al. 2010 ). However, some secondary outcomes, such as the degree of dyspnoea and quality of life, showed minor differences in favour of sildenafil. Another study on a combination of sildenafil and pirfenidone did not show any beneficial effect in preventing pulmonary hypertension associated with IPF (Behr et al. 2021 ). A prospective, randomized, double-blind, placebo-controlled, parallel-group, event-driven, morbidity–mortality clinical trial of bosentan, (an endothelin receptor antagonist) was conducted on 616 patients to investigate the benefit of modulating pulmonary hypertension associated with IPF (Giordano et al. 2010 ). However, bosentan failed to show any efficacy because there were no differences between treatment groups in health-related quality of life or dyspnoea (King et al. 2011 ).

Some of the investigational drugs under clinical development are TD139, PLN-74809, PLN-74809, TRK-250, PRM-151, and pamrevlumab (Glass et al. 2022 ). The investigational drug TD139 is a small molecule inhibitor of galectin-3 (Hirani et al. 2021 ). Integrins are known to activate TGF-β and have a role in pulmonary fibrosis (Sheppard 2008 ). Developmental endothelial locus-1 (Del-1) is an endogenous inhibitor of TGF-β activation (Kim et al. 2020 ). The newer molecule PLN-74809, a dual selective inhibitor of integrins αVβ1/αVβ6, is an emerging drug of the future (Decaris et al. 2021 ). PLN-74809 inhibits the deposition of collagen in lung tissue by blocking TGF-β pathway and inhibiting phosphorylation of Smad-3. It has shown efficacy in clinical trials (Decaris et al. 2021 ). TRK-250, produces siRNA in the body, and targets TGF-β mRNA is in clinical trial phase-1 ( NCT03727802 ). PRM-151, a recombinant human serum amyloid P/pentraxin 2 (PTX2) (Raghu et al. 2019 ), is currently in phase-3 clinical trials ( NCT04552899 ). The monoclonal antibody pamrevlumab, which targets connective tissue growth factor (CTGF) is currently in phase-2 clinical trial (Richeldi et al. 2020 ).

Drug targets for thalidomide in pulmonary fibrosis

Anti-fibrotic action

The potential use of thalidomide in interstitial pulmonary diseases has been debated since early 2000s (Ye 2006 ). The immunomodulatory action of thalidomide was seen as a desirable attribute with a potential to treat and manage debilitating diseases such as IPF. In addition, over recent years, the antiangiogenic action of thalidomide has also gained the attention of researchers. Thalidomide is considered helpful in fibrotic diseases mainly due to its immunomodulatory, antiangiogenic, antioxidant and anti-inflammatory actions (Ye 2006 ). Thalidomide is being proven as antifibrotic in bleomycin-induced mouse model of pulmonary fibrosis (Tabata et al. 2007 ). Inhibition of TGF-β is the major mechanism reported. Furthermore, thalidomide downregulates α-SMA in human foetal lung fibroblasts (Choe et al. 2010 ). In bleomycin-induced pulmonary fibrosis, thalidomide downregulates p-JNK and α-SMA (Liu et al. 2014 ). Dong and colleagues (2017) demonstrated that thalidomide inhibits pulmonary fibrosis both in vitro and in vivo. The same group has also demonstrated that the activity is due to regulation of the enzyme thioredoxin reductase (Dong et al. 2017a ). A cell line-based study conducted on Human Embryonic Lung Fibroblasts (HELF) has established that thalidomide is capable of directly exerting an antifibrotic action by inhibiting the activity of connective tissue growth factor (CTGF). CTGF is responsible for cell transformation, angiogenesis, myofibroblast differentiation and even upregulated ECM synthesis in the fibroblasts (Wu et al. 2020 ). This study proved that it was safer to block CTGF using thalidomide, than to block TGF-β altogether to prevent the pro-fibrotic actions of TGF-β. Thalidomide has also shown antifibrotic activity in the kidneys of streptozotocin-induced diabetic rats via upregulating the phosphorylation of AMPKα and inhibiting the NF-ĸB and TGF-β1/Smad signalling pathways of inflammation (Zhang et al. 2018 ). Moreover, it has also prevented the epithelial-mesenchymal transformation (EMT) through TGF-β-induced Smad-independent pathways by suppressing the phosphorylation and activation of several downstream proteins such as ERK, p38, Akt, which ultimately reduce the expression of fibrotic factors such as collagen and α-SMA (Zhou et al. 2017 ). The process of EMT is also triggered by thalidomide, mediated by EGFL6/PAX6 axis (Tang et al. 2020 ). Thalidomide has proven to be helpful in diminishing the expression of fibronectin by preventing keloid formation, thus being beneficial in treating skin fibrosis (Liang et al. 2013 ). With this emerging body of evidence, thalidomide shows potential for use in preventing fibrotic progression in pulmonary fibrosis.

Immunomodulatory and anti-inflammatory actions

The pathological evolution of IPF is strongly regulated by the entry of inflammatory cytokines and inflammatory mediators, such as IL-6, IL-1β, TNF-α, and TGF-β, into the alveolar space (Akdis et al. 2016 ). Thalidomide exerts anti-inflammatory effect by selectively inhibiting the production of TNF-α and other cytokines such as IL-12p40, IL-18, and IL-8 produced by the alveoli macrophages upon stimulation (Sampaio et al. 1991 ; Ye 2006 ). Thalidomide shows immunomodulatory action by preventing the activation of immune cells such as Th1 cells and related cytokines (Horton and Hallowell 2012 ). Choe et al . reported that thalidomide successfully inhibits the ERK1/2 pathways of signalling, which are induced by TGF-β in bleomycin-induced pulmonary fibrosis in mice (Choe et al. 2010 ). TGF-β is an important marker of tissue fibrosis that regulates the production of ECM components such as fibronectin and collagen (Kim et al. 2018 ). Thalidomide inhibits the pathways downstream of TGF-β, such as p38/Smad signalling, ERK 1/2 signalling, and MAPK pathways, by preventing the phosphorylation and subsequent activation of the proteins involved in the pathways (Liang et al. 2013 ; Zhou et al. 2017 ). The recent findings on IMiDs such as lenalidomide and pomalidomide promote the recruitment of aromatase to cereblon, resulting in the degradation of aromatase by proteasomes in immune cells (Tochigi et al. 2020 ). El-Zahabi et al. 2020 , have synthesized more than 40 thalidomide analogues, which were immunomodulators and ameliorated human TNF-α, caspase-8 (CASP8), human vascular endothelial growth factor (VEGF) and nuclear factor-kappa-BP65 (NF-κBP65) in human colon cancer (HCT-116) cells. Further, these derivatives have been shown to be immunomodulatory anticancer agents (El-Zahabi et al. 2020 ).

Antiangiogenic action

Since the anti-angiogenic action of thalidomide was established in 1994, thalidomide has been considered a potential drug candidate for treating several types of cancers and other metabolic disorders that require the inhibition of blood supply to tumours, or correct a pathologic angiogenic state (Behl et al. 2017 ). In addition, it is possible to extend this theory to the treatment of IPF. The role of angiogenesis in IPF has been constantly debated. It is still unclear how the aberrant neovascularization in the alveolar epithelium is related to the progression of IPF. However, nintedanib, a tyrosine kinase inhibitor, shows its antifibrotic action by targeting vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF)-receptors, all of which are involved in angiogenic signalling pathways (Ackermann et al. 2017 ). This indicates the possibility of using thalidomide as an anti-angiogenic agent in the treatment of IPF. A study conducted by Tabata et al . reported successful prevention of bleomycin-induced pulmonary fibrosis in mice by the anti-angiogenic action of thalidomide. It was observed that thalidomide, in addition to inhibiting angiogenesis in mice lung tissue, also reduced the expression of IL-6, TGF-β 1 , VEGF, Ang-1 Ang-2, and COL1A1 mRNA (Tabata et al. 2007 ). Thalidomide targets epidermal growth factor-like domain multiple 6 (EGFL6) and inhibits angiogenesis through EGFL6/PAX6 axis (Tang et al. 2020 ). The effect of thalidomide on EGFL6 is mediated through cereblon protein interaction with protease Lon N-terminal peptide, and this process is mediated by proteasome (Tang et al. 2020 ). Thalidomide and other IMiDs have reportedly reduced cell migration and adhesion by inhibiting the VEGF receptor, thereby reducing the capillary density on fibrotic lesions (Domingo et al. 2020 ), demonstrating that thalidomide could possibly be used as an anti-angiogenic for managing IPF.

Cereblon inhibitory action

CRBN has been established as the main target of thalidomide and its analogues (Ito et al. 2010 ). On binding to CRBN , thalidomide inhibits the activity of the E3-ubiquitin ligase of the multiple-protein complex CRBN-DDB1-Cul4 (Shortt et al. 2013 ). Cereblon is also involved in the pathogenesis of IPF (Kang et al. 2021 ). Thalidomide and other IMiDs such as lenalidomide and pomalidomide inhibit the action of cereblon and allow the expression of AMPK (Yang et al. 2021 ). Inhibition of AMPK is one of the mechanisms by which metformin inhibits proliferation and differentiation of human foetal lung fibroblast (Gu et al. 2021 ; Chen et al. 2022 ). AMPK modulation through cereblon shows a protective action and slows down the growth of fibrogenic proteins such as fibronectin, collagen α-SMA. Further, AMPK is down-regulated by the CRL4A-CRBN axis through the polyubiquitination of AMPKα isoforms (Kwon et al. 2019 ). Thus, cereblon inhibition could be the significant mechanism in mitigating fibrosis.

Antioxidant action

There is compelling evidence to implicate oxidative stress as one of the molecular mechanisms in IPF. Oxidative stress occurs from the imbalance between generation of reactive oxygen species (ROS) and the body’s ability to detoxify them (Todd et al. 2012 ; Estornut et al. 2022 ). Antioxidant enzymes (such as superoxide dismutase (SOD), catalase, glutathione peroxidase), and malondialdehyde (MDA), in the tissue homogenate are the markers of oxidative stress (Tsikas 2017 ). MDA accounts for lipid peroxidation or the extent of tissue damage occurring at the alveolar basement membrane (Tsikas 2017 ). The current standard drug pirfenidone demonstrated to have good antioxidant defence in human pulmonary artery smooth muscle cells (HPASMCs) (Fois et al. 2018 ). Further, pirfenidone and nintedanib exert beneficial effects on oxidative stress markers in humans (Fois et al. 2020 ; Li et al. 2022a ; Wang and Qu 2022 ). In a study conducted by Dong et al. in 2017 , treatment with thalidomide significantly increased SOD and normalized MDA and ROS in bleomycin-induced mouse model of pulmonary fibrosis. In another study, thalidomide significantly reduced MDA and ROS to near normal, and SOD was increased (Dong et al. 2017a ). In IPF, the antioxidant defences are regulated significantly through the redox-sensitive transcription factor nuclear factor, erythroid-derived 2 (Nrf2) (Wang et al. 2022 ; Dong et al. 2022 ). The Nrf2 binds to specific antioxidant response elements (AREs), stimulates the antioxidant enzyme genes, and regulates their expression (Walters et al. 2008 ; Liu et al. 2019 ). An in vivo study conducted in a bleomycin-induced mice model demonstrated the abilities of pirfenidone to balance the antioxidant defence or regulate the oxidative stress through Nrf2/Bach1 equilibrium (Liu et al. 2017 ). Similarly, thalidomide attenuated radiation-induced pulmonary fibrosis through Nrf2-dependent downregulation of the TGF-β/Smad3 pathways (Bian et al. 2018 ). These studies suggest that thalidomide exerts its protective effect against pulmonary fibrosis by suppressing bleomycin-induced oxidative stress and the resulting damage to the membrane, thereby preventing inflammation.

Current status of preclinical and clinical studies

Over the past few years, there has been a lot of research on repurposing thalidomide in various disorders. However, its use is currently restricted to multiple myeloma and erythema nodosum leprosum. Table 1 represents 40 different studies with highly specific markers studied in IPF models. Despite abundant preclinical data on thalidomide acting against IPF, none have ventured into a clinical trial. Suboptimal confidence in thalidomide in a clinical setting could be attributed to teratogenic effects (Khalil et al. 2020 ). The multiple mechanisms of action of thalidomide in lung fibrosis urged us to produce this comprehensive report. Anti-inflammatory, immunomodulatory, and anti-angiogenic actions of thalidomide have been shown to be benefit management of aberrant inflammatory responses in IPF. The TNF-α-inhibitory and antifibrotic activity of thalidomide could help mitigate the harmful effects from the abnormal wound healing process during IPF. TGF-β inhibition halts the fibrosis process or progression of the disease (Ye and Hu 2021 ). See Table 1 for multiple mechanisms of action reported in preclinical and clinical studies, supporting the preventive effect of thalidomide in lung fibrosis. Table 1 Preclinical and clinical trials performed to assess thalidomide / its analogues and their mechanism of action (data are in chronological order) Sl. no Description of study/Mechanism of action Author/References 1 Thalidomide reduced inflammatory markers such as TNF-α, IL-12p40, IL-18, and IL-8 in bronchoalveolar lavage fluid (BALF) of patients with IPF (Ye 2006 ) 2 Thalidomide reduced the expression of IL-6, TGF-β1, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in bleomycin-induced mouse model of pulmonary fibrosis (Tabata et al. 2007 ) 3 Thalidomide was used to treat cough in IPF patients. Discontinuation of thalidomide resulted in a return of cough within two weeks. Thalidomide is still used as a last resort, when other drugs fail (Horton et al. 2008 ) 4 Thalidomide reported to be beneficial in treating IPF in human foetal lung fibroblasts and bleomycin-induced mouse model of pulmonary fibrosis. The mechanisms of action implied were TGF-β pathway and downregulation of α-SMA (Zhao et al. 2009 ) 5 Thalidomide reportedly inhibited nitric oxide (NO) in mice model of pulmonary fibrosis (Nematbakhsh et al. 2009 ) 6 Thalidomide ameliorated the symptoms of bleomycin-induced mouse model of pulmonary fibrosis through TGF-β and ERK1/2 pathways (Choe et al. 2010 ) 7 Thalidomide inhibited experimental peritoneal fibrosis in mice by ameliorating sub-mesothelial thickening and angiogenesis, reducing PCNA- and VEGF-expressing cells, myofibroblasts, and TGF-β-positive cells (Arai et al. 2011 ) 8 Thalidomide was reported to reduce inflammatory mediators in BALF in IPF patients in China. This report is a first-of-its-kind in human IPF (Zhang and Yang 2012 ) 9 Cough and QoL were significantly improved, although adverse effects such as discomfort, dizziness and constipation were reported in a randomized trial involving 98 patients treated with thalidomide (Horton et al. 2012 ) 10 Thalidomide had anti-inflammatory effect in paraquat-induced mouse lung inflammation. It showed reduction of IL-1β, IL-6, TGF)-β1, myeloperoxidase (MPO), NO, and hydroxyproline levels (Amirshahrokhi 2013 ) 11 Thalidomide suppressed the inflammatory pathway in the lungs and reduced the release of cytokines and interferons in H1N1-infected BALB/c mice (Zhu et al. 2014 ) 12 Thalidomide inhibited bleomycin-induced pulmonary fibrosis in rats by downregulating p-JNK and α-SMA (Liu et al. 2014 ) 13 Five thalidomide dithioate analogues showed anti-inflammatory activity by inhibiting TNF-α, NF-κB, and showed free radical scavenging activity by oxygen radical antioxidant capacity (ORAC) and NO inhibition assay (Talaat et al. 2015 ) 14 Thalidomide attenuated cisplatin-induced nephrotoxicity, possibly by inhibition of inflammatory reactions (TNF-α, IL-1β, IL-6, TGF-β1, lipid peroxidation, MPO and NO) in the experimental model (Amirshahrokhi and Khalili 2015 ) 15 Thalidomide decreased the levels of TNF-α, TGF-β, COL1A1, IL-6 in lung fibrosis by paraquat in Wistar rats (Li et al. 2015 ) 16 Thalidomide inhibited inflammation by inhibiting cytokines (TNF-α, IL-1β, IL-6, IL-10 and IL-17) and chemokines such as Keratinocyte chemoattractant (KC), monokine induced by interferon-γ (MIG), and basic fibroblast growth factor (bFGF) in unilateral ureter obstruction (Bersani-Amado et al. 2016 ) 17 Thalidomide showed anti-lung fibrosis effect in rat models chiefly by anti-inflammatory and antioxidant effects via regulation of thioredoxin reductase (Dong et al. 2017a ) 18 Thalidomide acted through iNOS and nitric oxide pathways when tested for antinociceptive effects (Khan et al. 2017 ) 19 Thalidomide was shown to inhibit lung fibrosis both in vivo and in cell lines, chiefly by anti-inflammatory and antioxidant mechanisms (Dong et al. 2017b ) 20 Anti-fibrotic action of thalidomide was through TGF-β1 mechanism and preventing EMT in alveolar epithelial cells through both, Smad-dependent and Smad-independent pathways (Zhou et al. 2017 ) 21 Thalidomide analogues exerted anticancer activity in human lung cancer A549 cells through inhibiting VEGF and MMP-3 (El-Aarag et al. 2017 ) 22 Thalidomide improved psoriasis-like lesions and inhibited the expression of cutaneous VEGF in the imiquimod-induced psoriatic mouse model (BALB/c mice) (Liu et al. 2018 ) 23 Thalidomide suppressed renal fibrotic proteins, (E.g.TGF-β1, TβRII, TβRI, smad3, collagen IV, fibronectin) and stimulated the phosphorylation of AMPKα in rats with diabetic nephropathy (Zhang et al. 2018 ) 24 Thalidomide decreased ROS levels by inhibition of TGF-β/Smad3 pathway in radiation-induced lung fibrosis in mice (Bian et al. 2018 ) 25 Thalidomide attenuated the development of morphine dependence by inhibition of PI3K/Akt and NO signalling pathways in NMRI mice and human glioblastoma T98G cells (Khan et al. 2018 ) 26 Pomalidomide was tested for safety and efficacy (phase-2 trial) in interstitial lung disease due to systemic sclerosis,However, pomalidomide did not show statistical significance (Hsu et al. 2018 ) 27 Thalidomide down-regulated COX-2 expression in epithelial cells and collagen synthesis, and reduced cough by acting on sensory nerves of the respiratory tract. The test was done in bleomycin-induced lung fibrosis in C57BL/6 mice model (Rezaie et al. 2019 ) 28 Thalidomide decreased IFN-γ, IGF-1, IL-6, IL-17, TNF-α, while increasing the levels of IL-10 and TGF-γ. It down-regulated the expression of col1a2, col3a2, MMP-3, MMP-9, MMP-1, TGF-γ, α-SMA, but upregulated the expression of TIMP-1 and Vimentin in TNBS-induced mice colitis (Chen et al. 2019a ) 29 Thalidomide inhibited NO, TNF-α and IL-6 production, reducing portal pressure and increasing the expression of suppressor of cytokine signalling 1 (SOCS1) to prevent cirrhotic cardiomyopathy in rats (Hosseini-Chegeni et al. 2019 ) 30 Thalidomide prevented bleomycin-induced systemic sclerosis in a mouse model, acting through TGF-β1/Smad3 pathway. Systemic sclerosis is a type of autoimmune skin fibrosis (Lu et al. 2020 ) 31 Thalidomide inhibited the gene promoter activation of CTGF induced by TGF-β1 in human embryonic lung fibroblasts (HELF) (Wu et al. 2020 ) 32 Low-dose thalidomide reduced the hyperinflammatory state and calmed down a 45 year-old woman without adverse effects, when given as an adjuvant, with a short-term glucocorticoid, to treat severe lung injury due to COVID-19 (Chen et al. 2020 ) 33 Thalidomide upregulated T-cell transcriptor (T-bet) in natural killer (NK) cells and down-regulated glycogen synthase kinase-3β (GSK-3β) expression to inhibit lung metastasis of cancer cells (Miyazato et al. 2020 ) 34 Thalidomide analogue 6-{4-[(3-(1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}hexanoic acid (10e) reversed the migratory ability of TGF-β1-induced myofibroblasts, dedifferentiated myofibroblasts to fibroblasts due to cytoskeleton remodelling, and restrained myofibroblast activation by targeting Orai1 and TGF-β1/Smad2/3 signalling pathways (Tang et al. 2021 ) 35 Thalidomide, but not lenalidomide or pomalidomide, upregulated spinal microglial IL-10 / β-endorphin expression, to alleviate neuropathic pain (Deng et al. 2021 ) 36 Thalidomide suppressed VEGF and Ang-2-induced cell migration and capillary-like tube formation in human umbilical vein endothelial cells (HUVECs). This suggests that thalidomide inhibits angiogenesis via downregulation of VEGF and angiopoietin-2 in Crohn's Disease (Wang et al. 2021 ) 37 Thalidomide protected against paraquat-induced lung injury through a miRNA-141/HDAC6/IκBα-NF-κB axis in rat lung fibrosis model and in the RLE-6TN cell model (Zheng et al. 2021 ) 38 Thalidomide modulated ER-stress, through TLR4- NF-κB pathway in mouse model of silicosis. Silicosis is a common form of pulmonary fibrosis in China (Li et al. 2022b ) 39 Thalidomide derivative CC-885 was found to be a Basonuclin 2 (BNC2) inhibitor. The transcript BCN2 is responsible for simulating fibrosis signalling in tissues (Bobowski-Gerard et al. 2022 ) 40 Thalidomide effectively lowered skin lesions, inflammation and fibrosis related factors in rosacea mice model (Kang et al. 2022 )

Currently approved drugs for IPF are pirfenidone and nintedanib, with similar pros and cons. Pirfenidone is not preferred in case of comorbidities such as renal end-stage disease, because 80% of its clearance is via renal route. Similarly, nintedanib is not recommended for moderate to severe hepatic impairment because most of its metabolism and excretion occur within the hepatic system (Morrow et al. 2022 ). However, the preference for selection between pirfenidone and nintedanib is based on the patient’s preference on dosing, the adverse drug reactions (ADRs), cost, and insurance coverage (Morrow et al. 2022 ). Pirfenidone produces ADRs such as nausea, rash, abdominal pain, upper respiratory infection, diarrhoea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease (GERD), sinusitis, insomnia, weight loss, and arthralgia (Galli et al. 2017 ). A combination of pirfenidone with thalidomide has the advantage of mitigating these ADRs. Along with anti-emetic activity, thalidomide has a sedative effect and improves sleep patterns in patients with lung fibrosis (Horton et al. 2012 ). A recent case study of an IPF patient treated with thalidomide for cough suppression showed an improvement in the patient condition, especially in tackling cough (Haraf et al. 2018 ). However, the efficacy of relieving or reversing fibrosis has not been tested in the case. Although thalidomide has been used for treating cough in IPF, it is only used when other drugs fail. The recently published case study is one such example (Haraf et al. 2018 ). Previously, a randomized study included only 24 patients with IPF and cough (Horton et al. 2012 ), and another study had only 11 patients having cough in IPF (Horton et al. 2008 ). The recent meta-analysis on thalidomide did not include data from patients with IPF (Xie et al. 2022 ). Thus, thalidomide has not yet undergone thorough clinical investigations owing to its teratogenic history. The preclinical effect of thalidomide is mainly mediated by inhibition of TFG-β, TNF-α, ILs and by antioxidant mechanisms. Significant advancement in diagnosis and prognosis of IPF, and availability of improved biomarkers for statistical comparison of therapeutic output, make clinical trials appropriate and timely (Chen et al. 2019b ; Christe et al. 2019 ; Hochhegger et al. 2019 ; Tomassetti et al. 2020 ). Hence, based on the above highlights, we propose a prospective clinical investigation for thalidomide in the treatment of IPF.

Conclusion

There has been significant progress in thalidomide research, paving the way for its potential repurposing in inflammatory and neoplastic conditions. Thalidomide, which had once been revoked of its title of wonder drug, has managed to find a place in healthcare for the treatment of multiple myeloma and erythema nodosum leprosum. Despite the uncertainty regarding its potential in pulmonary fibrosis, a growing body of evidence substantiates the rationale of repurposing thalidomide for treating and slowing down the onset of fibrosis. The discovery of the thalidomide-binding protein, cereblon, was a breakthrough study that helped understand, to a certain extent, the mechanism of action of thalidomide at the molecular level. With recent information on the role of cereblon in the progression of IPF and newer biomarkers established for clinical trial assessments, thalidomide will have a promising role in preventing fibrosis, warranting future investigations.

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Acknowledgements

The authors thank BioRender software used in creating the figures and visualisations. The authors express their gratitude to M K Unnikrishnan, Professor, NGSM Institute of Pharmaceutical Sciences, Nitte University, for mentoring, revising and helping to correct the scientific writing.

Author contributions

CRediT authorship contribution statement. NND: Conceptualization, Methodology, Visualisation, Data Curation, Writing—Original Draft. VA: Methodology, Data collections, Visualisation, Writing—Original Draft. KB: Formal analysis, Writing—Review and Editing. SM: Methodology, Formal analysis. BHB: Methodology, Formal analysis. YN: Conceptualization, Resources, Data Curation, Visualisation, Writing—Review and Editing.

Funding

Open access funding provided by Manipal Academy of Higher Education, Manipal. There was no funding support for this work.

Data availability

As this is a review manuscript, there is no data generated.

Declarations

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence in publishing this paper.

Ethics approval

There was no human or animal studies involved.

References

Ackermann M Kamp JC Werlein C The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling EBioMedicine 2022 85 104296 10.1016/j.ebiom.2022.104296 36206625 PMC9535314

Ackermann M Kim YO Wagner WL Effects of nintedanib on the microvascular architecture in a lung fibrosis model Angiogenesis 2017 20 359 372 10.1007/s10456-017-9543-z 28283856 PMC7412751

Akdis M Aab A Altunbulakli C Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases J Allergy Clin Immunol 2016 138 984 1010 10.1016/j.jaci.2016.06.033 27577879

Al-kuraishy HM Batiha GE-S Faidah H Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals Inflammopharmacology 2022 30 2017 2026 10.1007/s10787-022-01027-6 36044102 PMC9430017

Amare GG Meharie BG Belayneh YM A drug repositioning success: the repositioned therapeutic applications and mechanisms of action of thalidomide J Oncol Pharm Pract 2021 27 673 678 10.1177/1078155220975825 33249990

Amirshahrokhi K Anti-inflammatory effect of thalidomide in paraquat-induced pulmonary injury in mice Int Immunopharmacol 2013 17 210 215 10.1016/j.intimp.2013.06.005 23810410

Amirshahrokhi K Khalili A-R Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model Inflammation 2015 38 476 484 10.1007/s10753-014-9953-7 24950782

Arai H Furusu A Nishino T Thalidomide prevents the progression of peritoneal fibrosis in mice Acta Histochem Cytochem 2011 44 51 60 10.1267/ahc.10030 21614166 PMC3096082

Asatsuma-Okumura T Ando H De Simone M p63 is a cereblon substrate involved in thalidomide teratogenicity Nat Chem Biol 2019 15 1077 1084 10.1038/s41589-019-0366-7 31591562

Asatsuma-Okumura T Ito T Handa H Molecular mechanisms of cereblon-based drugs Pharmacol Ther 2019 202 132 139 10.1016/j.pharmthera.2019.06.004 31202702

Asatsuma-Okumura T Ito T Handa H Molecular mechanisms of the teratogenic effects of thalidomide Pharmaceuticals 2020 13 95 10.3390/ph13050095 32414180 PMC7281272

Barbarossa A Iacopetta D Sinicropi MS Recent advances in the development of thalidomide-related compounds as anticancer drugs Curr Med Chem 2022 29 19 40 10.2174/0929867328666210623143526 34165402

Barratt S Creamer A Hayton C Chaudhuri N Idiopathic pulmonary fibrosis (IPF): an overview J Clin Med 2018 7 201 10.3390/jcm7080201 30082599 PMC6111543

Behl T Kaur I Goel H Kotwani A Significance of the antiangiogenic mechanisms of thalidomide in the therapy of diabetic retinopathy Vascul Pharmacol 2017 92 6 15 10.1016/J.VPH.2015.07.003 26196302

Behr J Nathan SD Wuyts WA Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial Lancet Respir Med 2021 9 85 95 10.1016/S2213-2600(20)30356-8 32822614

Bersani-Amado LE Dantas JA Damião MJ Involvement of cytokines in the modulation and progression of renal fibrosis induced by unilateral ureteral obstruction in C57BL/6 mice: effects of thalidomide and dexamethasone Fundam Clin Pharmacol 2016 30 35 46 10.1111/fcp.12162 26501392

Bian C Qin W-J Zhang C-Y Thalidomide (THD) alleviates radiation induced lung fibrosis (RILF) via down-regulation of TGF-β/Smad3 signaling pathway in an Nrf2-dependent manner Free Radic Biol Med 2018 129 446 453 10.1016/j.freeradbiomed.2018.10.423 30339882

Blaschke G Kraft HP Fickentscher K Köhler F Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers Arzneimittel-Forschung/drug Res 1979 29 1640 1642 583234

Bobowski-Gerard M Boulet C Zummo FP Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis Nat Commun 2022 13 5324 10.1038/s41467-022-33063-9 36088459 PMC9464213

Brandenburg NA Bwire R Freeman J Effectiveness of risk evaluation and mitigation strategies (REMS) for lenalidomide and thalidomide: patient comprehension and knowledge retention Drug Saf 2017 40 333 341 10.1007/s40264-016-0501-2 28074423 PMC5362654

Burman A Tanjore H Blackwell TS Endoplasmic reticulum stress in pulmonary fibrosis Matrix Biol 2018 68–69 355 10.1016/J.MATBIO.2018.03.015 29567124 PMC6392005

Cameli P Refini RM Bergantini L Long-term follow-up of patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib: a real-life comparison study Front Mol Biosci 2020 10.3389/fmolb.2020.581828 33102528 PMC7498677

Chang X-B Keith Stewart A What is the functional role of the thalidomide binding protein cereblon? Int J Biochem Mol Biol 2011 2 287 294 22003441 PMC3193296

Chen C Qi F Shi K Thalidomide combined with low-dose short-term glucocorticoid in the treatment of critical Coronavirus Disease 2019 Clin Transl Med 2020 10 e35 10.1002/ctm2.35 32508009 PMC7403664

Chen H Xu H Luo L Thalidomide prevented and ameliorated pathogenesis of Crohn’s disease in mice via regulation of inflammatory response and fibrosis Front Pharmacol 2019 10.3389/fphar.2019.01486 31920668 PMC6923734

Chen L Halai V Leandru A Wallis A Interstitial lung disease: update on the role of computed tomography in the diagnosis of idiopathic pulmonary fibrosis J Comput Assist Tomogr 2019 43 898 905 10.1097/RCT.0000000000000915 31453976

Chen Q Wang Y Sheng L Huang Y Metformin suppresses proliferation and differentiation induced by BMP9 via AMPK signaling in human fetal lung fibroblast-1 Front Pharmacol 2022 10.3389/fphar.2022.984730 36091775 PMC9448853

Cheng D Xu Q Wang Y Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling J Transl Med 2021 19 1 18 10.1186/S12967-021-03036-5/FIGURES/9 34399790 PMC8365894

Choe J-Y Jung H-J Park K-Y Anti-fibrotic effect of thalidomide through inhibiting TGF-β-induced ERK1/2 pathways in bleomycin-induced lung fibrosis in mice Inflamm Res 2010 59 177 188 10.1007/s00011-009-0084-9 19757088

Choi SM Jang AH Kim H Metformin reduces bleomycin-induced pulmonary fibrosis in mice J Korean Med Sci 2016 31 1419 1425 10.3346/JKMS.2016.31.9.1419 27510385 PMC4974183

Choi T-Y Lee S-H Kim Y-J Cereblon maintains synaptic and cognitive function by regulating BK channel J Neurosci 2018 38 3571 3583 10.1523/JNEUROSCI.2081-17.2018 29530986 PMC6596048

Christe A Peters AA Drakopoulos D Computer-aided diagnosis of pulmonary fibrosis using deep learning and CT images Invest Radiol 2019 54 627 632 10.1097/RLI.0000000000000574 31483764 PMC6738634

Cinausero M Aprile G Ermacora P New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury Front Pharmacol 2017 10.3389/fphar.2017.00354 28642709 PMC5462992

Cooper CR Poindexter C Rohe B Sikes RA Thalidomide and its analogues in prostate cancer therapy—a scientific update Biochem (lond) 2010 32 36 39 10.1042/bio03205036

D’Amato RJ Loughnan MS Flynn E Folkman J Thalidomide is an inhibitor of angiogenesis Proc Natl Acad Sci 1994 91 4082 4085 10.1073/pnas.91.9.4082 7513432 PMC43727

Daccord C Maher TM Recent advances in understanding idiopathic pulmonary fibrosis F1000Research 2016 5 1046 10.12688/f1000research.8209.1 PMC4890320 27303645

Decaris ML Schaub JR Chen C Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF Respir Res 2021 22 265 10.1186/s12931-021-01863-0 34666752 PMC8524858

Deng M-Y Ahmad KA Han Q-Q Thalidomide alleviates neuropathic pain through microglial IL-10/β-endorphin signaling pathway Biochem Pharmacol 2021 10.1016/j.bcp.2021.114727 34390739

Denver C Eickelberg UO Schwarz MI Schwartz DA Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? Lancet Respir Med 2018 6 154 160 10.1016/S2213-2600(18)30007-9 29413083 PMC5903445

Diaz de Leon A, Cronkhite JT, Katzenstein A-LA, et al (2010) Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations. PLoS One 5:e10680. 10.1371/journal.pone.0010680 10.1371/journal.pone.0010680 PMC2873288 20502709

Domingo S Solé C Moliné T Efficacy of thalidomide in discoid lupus erythematosus: insights into the molecular mechanisms Dermatology 2020 236 467 476 10.1159/000508672 32659758

Dong X Li X Li M Inhibitory effects of thalidomide on bleomycin-induced pulmonary fibrosis in rats via regulation of thioredoxin reductase and inflammations Am J Transl Res 2017 9 4390 4401 29118902 PMC5666049

Dong X Li X Li M Antiinflammation and antioxidant effects of thalidomide on pulmonary fibrosis in mice and human lung fibroblasts Inflammation 2017 40 1836 1846 10.1007/s10753-017-0625-2 28730510

Dong Z Yin EG Yang M Role and mechanism of keap1/nrf2 signaling pathway in the regulation of autophagy in alleviating pulmonary fibrosis Comput Intell Neurosci 2022 2022 1 9 10.1155/2022/3564871 PMC9313964 35898772

El-Aarag B Kasai T Masuda J Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 Biomed Pharmacother 2017 85 549 555 10.1016/j.biopha.2016.11.063 27889230

El-Zahabi MA Sakr H El-Adl K Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents Bioorg Chem 2020 104 104218 10.1016/j.bioorg.2020.104218 32932121

Estornut C Milara J Bayarri MA Targeting oxidative stress as a therapeutic approach for idiopathic pulmonary fibrosis Front Pharmacol 2022 10.3389/fphar.2021.794997 35126133 PMC8815729

Fois AG Posadino AM Giordo R Antioxidant activity mediates pirfenidone antifibrotic effects in human pulmonary vascular smooth muscle cells exposed to sera of idiopathic pulmonary fibrosis patients Oxid Med Cell Longev 2018 10.1155/2018/2639081 30420906 PMC6215550

Fois AG Sotgiu E Scano V Effects of pirfenidone and nintedanib on markers of systemic oxidative stress and inflammation in patients with idiopathic pulmonary fibrosis: a preliminary report Antioxidants 2020 9 1 15 10.3390/antiox9111064 PMC7692317 33143144

Furihata H Yamanaka S Honda T Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide Nat Commun 2020 10.1038/s41467-020-18488-4 32929090 PMC7490372

Galli JA Pandya A Vega-Olivo M Pirfenidone and nintedanib for pulmonary fibrosis in clinical practice: tolerability and adverse drug reactions Respirology 2017 22 1171 1178 10.1111/resp.13024 28317233

Gao S Wang S Fan R Hu J Recent advances in the molecular mechanism of thalidomide teratogenicity Biomed Pharmacother 2020 127 110114 10.1016/j.biopha.2020.110114 32304852

Giordano N Puccetti L Papakostas P Bosentan treatment for Raynauds phenomenon and skin fibrosis in patients with systemic sclerosis and pulmonary arterial hypertension: an open-label, observational, retrospective study Int J Immunopathol Pharmacol 2010 23 1185 1194 10.1177/039463201002300422 21244767

Glass DS Grossfeld D Renna HA Idiopathic pulmonary fibrosis: current and future treatment Clin Respir J 2022 10.1111/crj.13466 35001525 PMC9060042

Gu X Han YY Yang CY Activated AMPK by metformin protects against fibroblast proliferation during pulmonary fibrosis by suppressing FOXM1 Pharmacol Res 2021 173 105844 10.1016/J.PHRS.2021.105844 34450310

Gutiérrez-Rodríguez O Thalidomide a promising new treatment for rheumatoid arthritis Arthritis Rheum 1984 27 1118 1121 10.1002/art.1780271006 6237660

Gutierrez-Rodriguez O Starusta-Bacal P Gutierrez-Montes O Treatment of refractory rheumatoid arthritis - the thalidomide experience J Rheumatol 1989 16 158 163 2746563

Hamza MH Treatment of Behçet’s disease with thalidomide Clin Rheumatol 1986 5 365 371 10.1007/BF02054255 3780143

Hansen JM Gong S-G Philbert M Harris C Misregulation of gene expression in the redox-sensitive NF-?b-dependent limb outgrowth pathway by thalidomide Dev Dyn 2002 225 186 194 10.1002/dvdy.10150 12242718

Haraf R Flora AS Assaly R Thalidomide as a cough suppressant in idiopathic pulmonary fibrosis Am J Ther 2018 25 E687 E688 10.1097/MJT.0000000000000695 29232284

Hirani N MacKinnon AC Nicol L Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis Eur Respir J 2021 10.1183/13993003.02559-2020 33214209 PMC8156151

Hochhegger B Marchiori E Zanon M Imaging in idiopathic pulmonary fibrosis: diagnosis and mimics Clinics 2019 10.6061/clinics/2019/e225 30726312 PMC6384526

Holstein SA McCarthy PL Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience Drugs 2017 77 505 520 10.1007/s40265-017-0689-1 28205024 PMC5705939

Horton MR Danoff SK Lechtzin N Thalidomide inhibits the intractable cough of idiopathic pulmonary fibrosis Thorax 2008 63 749 10.1136/thx.2008.098699 18663075

Horton MR Hallowell RW Revisiting thalidomide: fighting with caution against idiopathic pulmonary fibrosis Drugs Today 2012 48 661 671 10.1358/dot.2012.48.10.1855760 23110262

Horton MR Santopietro V Mathew L Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial Ann Intern Med 2012 157 398 406 10.7326/0003-4819-157-6-201209180-00003 22986377

Hosseini-Chegeni A Jazaeri F Yousefi-Ahmadipour A Thalidomide attenuates the hyporesponsiveness of isolated atria to chronotropic stimulation in BDL rats: The involvement of TNF-α, IL-6 inhibition, and SOCS1 activation Iran J Basic Med Sci 2019 22 1259 1266 32128089 10.22038/ijbms.2019.32256.7742 PMC7038422

Hsu VM Denton CP Domsic RT Pomalidomide in patients with interstitial lung disease due to systemic sclerosis: a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study J Rheumatol 2018 45 405 410 10.3899/jrheum.161040 29093152

Ito T Ando H Handa H Teratogenic effects of thalidomide: molecular mechanisms Cell Mol Life Sci 2011 68 1569 1579 10.1007/s00018-010-0619-9 21207098 PMC11114848

Ito T Ando H Suzuki T Identification of a primary target of thalidomide teratogenicity Science 2010 80 327 1345 1350 10.1126/science.1177319 20223979

Ito T Handa H Deciphering the mystery of thalidomide teratogenicity Congenit Anom (Kyoto) 2012 52 1 7 10.1111/j.1741-4520.2011.00351.x 22348778

Ito T Handa H Molecular mechanisms of thalidomide and its derivatives Proc Japan Acad Ser B Phys Biol Sci 2020 96 189 203 10.2183/PJAB.96.016 PMC7298168 32522938

Jung YJ Tweedie D Scerba MT Repurposing immunomodulatory imide drugs (IMiDs) in neuropsychiatric and neurodegenerative disorders Front Neurosci 2021 10.3389/fnins.2021.656921 33854417 PMC8039148

Kang HJ Lee KJ Woo J Cereblon contributes to the development of pulmonary fibrosis via inactivation of adenosine monophosphate-activated protein kinase α1 Exp Mol Med 2021 53 885 893 10.1038/s12276-021-00619-6 34002012 PMC8178361

Kang Y Zhang C He Y Thalidomide attenuates skin lesions and inflammation in rosacea-like mice induced by long-term exposure of LL-37 Drug Des Devel Ther 2022 16 4127 4138 10.2147/DDDT.S393122 36483458 PMC9724583

Kärkkäinen M Kettunen H-P Nurmi H Effect of smoking and comorbidities on survival in idiopathic pulmonary fibrosis Respir Res 2017 18 160 10.1186/s12931-017-0642-6 28830514 PMC5567897

Kawamura Y Yamashita T Yamauchi T Effects of thalidomide on Fgf8, Bmp4 and Hoxa11 expression in the limb bud in Kbl: JW rabbit embryos Congenit Anom (kyoto) 2014 54 54 62 10.1111/cga.12046 24344727

Khalil A Kamar A Nemer G Thalidomide-revisited: are COVID-19 patients going to be the latest victims of yet another theoretical drug-repurposing? Front Immunol 2020 11 1248 10.3389/FIMMU.2020.01248/BIBTEX 32574274 PMC7270289

Khan MI Momeny M Ostadhadi S Thalidomide attenuates development of morphine dependence in mice by inhibiting PI3K/Akt and nitric oxide signaling pathways Prog Neuro-Psychopharmacol Biol Psychiatry 2018 82 39 48 10.1016/j.pnpbp.2017.12.002 29223784

Khan MI Ostadhadi S Mumtaz F Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through L-arginine-iNOS and nitric oxide pathway Biomed Pharmacother 2017 85 493 502 10.1016/j.biopha.2016.11.056 27899254

Kim D-Y Lee S-H Fu Y Del-1 an endogenous inhibitor of TGF-β activation attenuates fibrosis Front Immunol 2020 10.3389/fimmu.2020.00068 32117240 PMC7018852

Kim HK Ko TH Nyamaa B Cereblon in health and disease Pflügers Arch - Eur J Physiol 2016 468 1299 1309 10.1007/s00424-016-1854-1 27343012

Kim JH Scialli AR Thalidomide: the tragedy of birth defects and the effective treatment of disease Toxicol Sci 2011 122 1 6 10.1093/toxsci/kfr088 21507989

Kim KK Sheppard D Chapman HA TGF-β1 signaling and tissue fibrosis Cold Spring Harb Perspect Biol 2018 10.1101/cshperspect.a022293 28432134 PMC5880172

King TE Brown KK Raghu G BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis Am J Respir Crit Care Med 2011 184 92 99 10.1164/rccm.201011-1874OC 21474646

Kowalski TW Caldas-Garcia GB Gomes JDA Comparative genomics identifies putative interspecies mechanisms underlying crbn-sall4-linked thalidomide embryopathy Front Genet 2021 10.3389/fgene.2021.680217 34249098 PMC8262662

Kubo H Nakayama K Yanai M Anticoagulant therapy for idiopathic pulmonary fibrosis Chest 2005 128 1475 1482 10.1378/chest.128.3.1475 16162746

Kumar N Sharma U Singh C Singh B Thalidomide: chemistry, therapeutic potential and oxidative stress induced teratogenicity Curr Top Med Chem 2012 12 1436 1455 10.2174/156802612801784407 22650376

Kwon E Li X Deng Y AMPK is down-regulated by the CRL4A-CRBN axis through the polyubiquitination of AMPKα isoforms FASEB J 2019 33 6539 6550 10.1096/fj.201801766RRR 30807229

Lee KM Jo S Kim H Functional modulation of AMP-activated protein kinase by cereblon Biochim Biophys Acta Mol Cell Res 2011 1813 448 455 10.1016/J.BBAMCR.2011.01.005 21232561

Li D Zhang X-W Jiang X-Q Protective effects of thalidomide on pulmonary injuries in a rat model of paraquat intoxication J Inflamm (united Kingdom) 2015 10.1186/s12950-015-0093-0 PMC4517355 26221080

Li L Chen Y Shi C Nintedanib ameliorates oxidized low-density lipoprotein induced inflammation and cellular senescence in vascular endothelial cells Bioengineered 2022 13 6196 6207 10.1080/21655979.2022.2036913 35236245 PMC8974161

Li Y Cai W Jin F Thalidomide alleviates pulmonary fibrosis induced by silica in mice by inhibiting ER stress and the TLR4-NF-κB pathway Int J Mol Sci 2022 10.3390/ijms23105656 35628464 PMC9144898

Liang CJ Yen YH Hung LY Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway Biochem Pharmacol 2013 85 1594 1602 10.1016/J.BCP.2013.02.038 23500539

Liu JH Wu HH Zhao YK Thalidomide improves psoriasis-like lesions and inhibits cutaneous vegf expression without alteration of microvessel density in imiquimod-induced psoriatic mouse model Curr Vasc Pharmacol 2018 16 510 521 10.2174/1570161115666171004123428 28982338

Liu Q Gao Y Ci X Role of Nrf2 and its activators in respiratory diseases Oxid Med Cell Longev 2019 2019 1 17 10.1155/2019/7090534 PMC6341270 30728889

Liu X Qian L Nan H Function of the transforming growth factor-β1/c-Jun N-terminal kinase signaling pathway in the action of thalidomide on a rat model of pulmonary fibrosis Exp Ther Med 2014 7 669 674 10.3892/etm.2013.1457 24520265 PMC3919921

Liu Y Huang X He X A novel effect of thalidomide and its analogs: Suppression of cereblon ubiquitination enhances ubiquitin ligase function FASEB J 2015 29 4829 4839 10.1096/FJ.15-274050/-/DC1 26231201 PMC4653049

Liu Y Lu F Kang L Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium BMC Pulm Med 2017 10.1186/s12890-017-0405-7 28420366 PMC5395978

Lota HK Wells AU The evolving pharmacotherapy of pulmonary fibrosis Expert Opin Pharmacother 2013 14 79 89 10.1517/14656566.2013.758250 23265249

Lu Y Zhao C Lei L Effects of thalidomide on Th17, Treg cells and TGF-β1/Smad3 pathway in a mouse model of systemic sclerosis Int J Rheum Dis 2020 23 406 419 10.1111/1756-185X.13769 31840939

Luppi F Kalluri M Faverio P Idiopathic pulmonary fibrosis beyond the lung: understanding disease mechanisms to improve diagnosis and management Respir Res 2021 22 109 10.1186/s12931-021-01711-1 33865386 PMC8052779

Magnini D Montemurro G Iovene B Idiopathic pulmonary fibrosis: molecular endotypes of fibrosis stratifying existing and emerging therapies Respiration 2017 93 379 395 10.1159/000475780 28472808

Maher TM Bendstrup E Dron L Global incidence and prevalence of idiopathic pulmonary fibrosis Respir Res 2021 22 197 10.1186/s12931-021-01791-z 34233665 PMC8261998

Majumder S Rama Chaitanya Sreedhara S Banerjee S Chatterjee S TNF α signaling beholds thalidomide saga: a review of mechanistic role of TNF-α signaling under thalidomide Curr Top Med Chem 2012 12 1456 1467 10.2174/156802612801784443 22650377

Malouf MA Hopkins P Snell G Glanville A An investigator-driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis Respirology 2011 16 776 783 10.1111/j.1440-1843.2011.01955.x 21362103

Martinez FJ Collard HR Pardo A (2017) Idiopathic pulmonary fibrosis Nat Rev Dis Prim 2017 31 3 1 19 10.1038/nrdp.2017.74 29052582

Mellin GW Katzenstein M The saga of thalidomide - neuropathy to embryopathy, with case reports of congenital anomalies N Engl J Med 1962 267 1238 1244 10.1056/NEJM196212132672407 13934700

Michalski JE Schwartz DA Genetic risk factors for idiopathic pulmonary fibrosis: Insights into immunopathogenesis J Inflamm Res 2020 13 1305 1318 10.2147/JIR.S280958 33447070 PMC7801923

Miyazato K Tahara H Hayakawa Y Antimetastatic effects of thalidomide by inducing the functional maturation of peripheral natural killer cells Cancer Sci 2020 111 2770 2778 10.1111/cas.14538 32573072 PMC7419051

Morrow LE Hilleman D Malesker MA Management of patients with fibrosing interstitial lung diseases Am J Heal Pharm 2022 79 129 139 10.1093/ajhp/zxab375 PMC8881211 34608488

Mudawi D Heyes K Hastings R An update on interstitial lung disease Br J Hosp Med 2021 82 1 14 10.12968/hmed.2020.0556 34338019

Nayek U Basheer Ahamed SI Mansoor Hussain UH Computational investigations of indanedione and indanone derivatives in drug discovery: indanone derivatives inhibits cereblon, an E3 ubiquitin ligase component Comput Biol Chem 2022 10.1016/j.compbiolchem.2022.107776 36252444

Nematbakhsh M Rafieyan S Mirkheshti N Thalidomide reduces the level of nitric oxide in Bleomycin induced pulmonary fibrosis model Clin Exp Med Lett 2009 50 75 76

Newbronner E Glendinning C Atkin K Wadman R The health and quality of life of Thalidomide survivors as they age—evidence from a UK survey PLoS ONE 2019 10.1371/journal.pone.0210222 30650111 PMC6334953

Noth I Anstrom KJ Calvert SB A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis Am J Respir Crit Care Med 2012 10.1164/rccm.201202-0314OC 22561965 PMC3400994

Piura B Medina L Rabinovich A Thalidomide distinctly affected TNF-α, IL-6 and MMP secretion by an ovarian cancer cell line (SKOV-3) and primary ovarian cancer cells Eur Cytokine Netw 2013 24 122 129 10.1684/ecn.2013.0342 24284039

Raghu G Anstrom KJ King TE Jr Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis N Engl J Med 2012 366 1968 1977 10.1056/NEJMoa1113354 22607134 PMC3422642

Raghu G van den Blink B Hamblin MJ Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study Lancet Respir Med 2019 7 657 664 10.1016/S2213-2600(19)30172-9 31122893

Rangarajan S Bone NB Zmijewska AA Metformin reverses established lung fibrosis in a bleomycin model Nat Med 2018 24 1121 10.1038/S41591-018-0087-6 29967351 PMC6081262

Rehman W Arfons LM Lazarus HM The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development Ther Adv Hematol 2011 2 291 10.1177/2040620711413165 23556097 PMC3573415

Reyes-Terán G Sierra-Madero JG Martínez Del Cerro V Effects of thalidomide on HIV-associated wasting syndrome: a randomized, double-blind, placebo-controlled clinical trial AIDS 1996 10 1501 1507 10.1097/00002030-199611000-00007 8931784

Rezaie MJ Rostamzadeh A Keshavarz G Effect of Thalidomide on Cox-2 expression in bleomycin-induced pulmonary fibrosis in mice Biomed Res Ther 2019 6 2974 2982 10.15419/bmrat.v6i1.518

Richeldi L Collard HR Jones MG Idiopathic pulmonary fibrosis Lancet 2017 389 1941 1952 10.1016/S0140-6736(17)30866-8 28365056

Richeldi L Fernández Pérez ER Costabel U Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial Lancet Respir Med 2020 8 25 33 10.1016/S2213-2600(19)30262-0 31575509

Samel C Albus C Nippert I Life situation of women impaired by Thalidomide embryopathy in North Rhine-Westphalia—a comparative analysis of a recent cross-sectional study with earlier data BMC Womens Health 2019 19 51 10.1186/s12905-019-0745-y 30943953 PMC6448387

Sampaio EP Sarno EN Galilly R Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes J Exp Med 1991 173 699 703 10.1084/jem.173.3.699 1997652 PMC2118820

Sharma D Kwatra SG Thalidomide for the treatment of chronic refractory pruritus J Am Acad Dermatol 2016 74 363 369 10.1016/j.jaad.2015.09.039 26577510

Sheppard D The role of integrins in pulmonary fibrosis Eur Respir Rev 2008 17 157 162 10.1183/09059180.00010909

Sheskin J Thalidomide in the treatment of lepra reactions Clin Pharmacol Ther 1965 6 303 306 10.1002/cpt196563303 14296027

Shortt J Hsu AK Johnstone RW (2013) Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy Oncogene 2013 3236 32 4191 4202 10.1038/onc.2012.599 23318436

Tabata C Tabata R Kadokawa Y Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice J Immunol 2007 179 708 714 10.4049/jimmunol.179.1.708 17579094

Talaat R El-Sayed W Agwa HS Anti-inflammatory effect of thalidomide dithiocarbamate and dithioate analogs Chem Biol Interact 2015 238 74 81 10.1016/j.cbi.2015.05.017 26051520

Tang C-T Zhang Q-W Wu S Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation Cell Mol Life Sci 2020 77 5207 5221 10.1007/s00018-020-03465-3 32008086 PMC7671996

Tang KW Hsu WL Chen CR Discovery of triazolyl thalidomide derivatives as anti-fibrosis agents New J Chem 2021 45 3589 3599 10.1039/D0NJ03139A

Tanni SE Fabro AT de Albuquerque A Pulmonary fibrosis secondary to COVID-19: a narrative review Expert Rev Respir Med 2021 15 791 803 10.1080/17476348.2021.1916472 33902377

Tochigi T Miyamoto T Hatakeyama K Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug-induced thrombocytopenia Blood 2020 135 2146 2158 10.1182/blood.2019003749 32219443

Todd NW Luzina IG Atamas SP Molecular and cellular mechanisms of pulmonary fibrosis Fibrogenesis Tissue Repair 2012 5 11 10.1186/1755-1536-5-11 22824096 PMC3443459

Tokunaga E Yamamoto T Ito E Shibata N Understanding the thalidomide chirality in biological processes by the self-disproportionation of enantiomers Sci Rep 2018 8 17131 10.1038/s41598-018-35457-6 30459439 PMC6244226

Tomassetti S Ravaglia C Wells AU Prognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study Lancet Respir Med 2020 8 786 794 10.1016/S2213-2600(20)30122-3 32763205

Tsikas D Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges Anal Biochem 2017 524 13 30 10.1016/J.AB.2016.10.021 27789233

van Batenburg AA Kazemier KM van Oosterhout MFM From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis PLoS ONE 2020 15 e0226785 10.1371/journal.pone.0226785 31910222 PMC6946122

van Toorn R Zaharie S-D Seddon JA The use of thalidomide to treat children with tuberculosis meningitis: a review Tuberculosis 2021 10.1016/j.tube.2021.102125 34500217

Vargesson N Thalidomide-induced teratogenesis: history and mechanisms Birth Defects Res Part C Embryo Today Rev 2015 105 140 156 10.1002/bdrc.21096 PMC4737249 26043938

Velagacherla V Mehta CH Nayak Y Nayak UY Molecular pathways and role of epigenetics in the idiopathic pulmonary fibrosis Life Sci 2022 291 120283 10.1016/j.lfs.2021.120283 34998839

Walters DM Cho H-Y Kleeberger SR Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2 Antioxidants Redox Signal 2008 10 321 332 10.1089/ars.2007.1901 17999635

Wang C Qu L The anti-fibrotic agent nintedanib protects chondrocytes against tumor necrosis factor-ɑ (TNF-ɑ)-induced extracellular matrix degradation Bioengineered 2022 13 5318 5329 10.1080/21655979.2022.2036899 35164664 PMC8973871

Wang L Wang S Xue A Thalidomide inhibits angiogenesis via downregulation of VEGF and angiopoietin-2 in Crohn’s Disease Inflammation 2021 44 795 807 10.1007/s10753-020-01378-8 33206273

Wang Y Wei J Deng H The role of Nrf2 in pulmonary fibrosis: molecular mechanisms and treatment approaches Antioxidants 2022 10.3390/antiox11091685 36139759 PMC9495339

Wilson M Wynn T Pulmonary fibrosis: pathogenesis, etiology and regulation Mucosal Immunol 2009 2 103 10.1038/MI.2008.85 19129758 PMC2675823

Wu X Xiao X Chen X Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: a preclinical systematic review and meta-analysis Front Pharmacol 2022 10.3389/fphar.2022.948101 36147352 PMC9485720

Wu Y Liu L Zhang J Thalidomide inhibits the gene promoter of connective tissue growth factor in human embryonic lung fibroblasts Ann Palliat Med 2020 9 2516 2523 10.21037/apm-19-398 32819116

Wuyts WA Wijsenbeek M Bondue B Idiopathic pulmonary fibrosis: best practice in monitoring and managing a relentless fibrotic disease Respiration 2020 99 73 82 10.1159/000504763 31830755 PMC6979429

Xie J Zhang C Li S Efficacy and safety of thalidomide as a pre-medication of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (hec): a systematic review and meta-analysis Front Oncol 2022 10.3389/fonc.2021.818839 35141156 PMC8818791

Yang H Song Z Hong D CRBN knockdown mitigates lipopolysaccharide-induced acute lung injury by suppression of oxidative stress and endoplasmic reticulum (ER) stress associated NF-κB signaling Biomed Pharmacother 2020 123 109761 10.1016/J.BIOPHA.2019.109761 31865141

Yang S-J Jeon S Baek JW Regulation of AMPK activity by CRBN is independent of the thalidomide-CRL4CRBN protein degradation axis Pharmaceuticals 2021 10.3390/ph14060512 34073624 PMC8228114

Ye Q Thalidomide reduces IL-18, IL-8 and TNF- release from alveolar macrophages in interstitial lung disease Eur Respir J 2006 28 824 831 10.1183/09031936.06.00131505 16837501

Ye Z Hu Y TGF-β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (review) Int J Mol Med 2021 10.3892/ijmm.2021.4965 34013369 PMC8136122

Zhang H Yang Y Wang Y Renal-protective effect of thalidomide in streptozotocin-induced diabetic rats through anti-inflammatory pathway Drug Des Devel Ther 2018 12 89 10.2147/DDDT.S149298 29386886 PMC5765978

Zhang L Yang W-L Effect of thalidomide on the expressions of IL-6, TNF-α and TGF-β 1 in BALF of elder patients with idiopathic pulmonary fibrosis J xi’an Jiaotong Univ (medical) Sci. 2012 33 622 625

Zhao L Xiao K Wang H Thalidomide has a therapeutic effect on interstitial lung fibrosis: evidence from in vitro and in vivo studies Clin Exp Immunol 2009 157 310 315 10.1111/j.1365-2249.2009.03962.x 19604271 PMC2730857

Zheng F Zhu J Zhang W Thal protects against paraquat-induced lung injury through a microRNA-141/HDAC6/IκBα-NF-κB axis in rat and cell models Basic Clin Pharmacol Toxicol 2021 128 334 347 10.1111/bcpt.13505 33015978 PMC7894280

Zhou XL Xu P Chen HH (2017) Thalidomide inhibits TGF-β1-induced epithelial to mesenchymal transition in alveolar epithelial cells via smad-dependent and smad-independent signaling pathways Sci Reports 2017 71 7 1 10 10.1038/s41598-017-15239-2 PMC5677010 29116196

Zhu H Shi X Ju D Anti-Inflammatory effect of thalidomide on h1n1 influenza virus-induced pulmonary injury in mice Inflammation 2014 37 2091 2098 10.1007/s10753-014-9943-9 24912813

Zhu N Wang L Guo H Thalidomide suppresses angiogenesis through the signal transducer and activator of transcription 3/SP4 signaling pathway in the peritoneal membrane Front Physiol 2021 10.3389/fphys.2021.712147 34539435 PMC8446434

Zisman DA Schwarz M Anstrom KJ A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis N Engl J Med 2010 363 620 628 10.1056/NEJMoa1002110 20484178 PMC3587293