Repurposing drugs for solid tumor treatment:focus on immune checkpoint inhibitors

Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued,which therefore provides limited benefits to patients with cancer.Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed.Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest.This review comprehensively analyses the efficacy of various repurposed drugs,such as transforming growth factor-beta(TGF-β)inhibitors,metformin,receptor activator of nuclear factor-κB ligand(RANKL)inhibitors,granulocyte macrophage colony-stimulating factor(GM-CSF),thymosinα1(Tα1),aspirin,and bisphosphonate,in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy.Additionally,we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.

Parkinson’s disease and diabetes mellitus: common mechanisms and treatment repurposing

In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,plasticity,oxidative stress and neuroinflammation.Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide.Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms.Today,there are no available curative or disease modifying treatments for Parkinson’s disease,but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease,both in diabetic and nondiabetic Parkinsonian patients.Furthermore,it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease.Here,we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism,with a particular focus on glucagon-like peptide-1 receptor agonists.

Drug repurposing for cancer treatment through global propagation with a greedy algorithm in a multilayer network

Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.

Treatment repurposing for inflammatory bowel disease using literature-related discovery and innovation

Inflammatory bowel disease(IBD)incidence has been increasing steadily,most dramatically in the Western developed countries.Treatment often includes lifelong immunosuppressive therapy and surgery.There is a critical need to reduce the burden of IBD and to discover medical therapies with better efficacy and fewer potential side-effects.Repurposing of treatments originally studied in other diseases with similar pathogenesis is less costly and time intensive than de novo drug discovery.This study used a treatment repurposing methodology,the literature-related discovery and innovation(LRDI)text mining system,to identify potential treatments(developed for non-IBD diseases)with sufficient promise for extrapolation to treatment of IBD.By searching for desirable patterns of twenty key biomarkers relevant to IBD(e.g.,inflammation,reactive oxygen species,autophagy,barrier function),the LRDI-based query retrieved approximately 9500 records from Medline.The most recent 350 records were further analyzed for proof-of-concept.Approximately 18%(64/350)met the criteria for discovery(not previously studied in IBD human or animal models)and relevance for application to IBD treatment.Many of the treatments were compounds derived from herbal remedies,and the majority of treatments were being studied in cancer,diabetes,and central nervous system disease,such as depression and dementia.As further validation of the search strategy,the query identified ten treatments that have just recently begun testing in IBD models in the last three years.Literature-related discovery and innovation text mining contains a unique search strategy with tremendous potential to identify treatments for repurposing.A more comprehensive query with additional key biomarkers would have retrieved many thousands more records,further increasing the yield of IBD treatment repurposing discovery.

Drug repurposing against coronavirus disease 2019(COVID-19):A review

Since December 2019,severe acute respiratory syndrome coronavirus 2 has been found to be the culprit in the coronavirus disease 2019(COVID-19),causing a global pandemic.Despite the existence of many vaccine programs,the number of confirmed cases and fatalities due to COVID-19 is still increasing.Furthermore,a number of variants have been reported.Because of the absence of approved anticoronavirus drugs,the treatment and management of COVID-19 has become a global challenge.Under these circumstances,drug repurposing is an effective method to identify candidate drugs with a shorter cycle of clinical trials.Here,we summarize the current status of the application of drug repurposing in COVID-19,including drug repurposing based on virtual computer screening,network pharmacology,and bioactivity,which may be a beneficial COVID-19 treatment.

Paracelsus Paradox and Drug Repurposing for Cancer

Dose is one of the parameters that any pharmacologist seriously considers when studying the effects of a drug.If the necessary dose to achieve a desired pharmacological effect is in a toxic or very toxic range for human use,the drug will probably fall out from further research.The concentration that a drug can reach to its target organ or cell is a direct consequence of the administered dose and its pharmacodynamic properties.Basic researchers investigate at the cellular level or eventually with xenografts.They use different concentrations of the drug in order to determine its cellular effects.However,in many cases,these concentrations require doses that are in the toxic range or well beyond any clinically achievable level.Therefore,in these cases,research is in the realm of toxicology rather than therapeutics.This paper will show some examples about this exercise in futility which is time and resource consuming but that pullulates the pages of many prestigious journals.Many seasoned researchers seem to have forgotten the Paracelsus Paradox.

An update review on drug repurposing for COVID-19

The COVID-19 global health disaster has caused more than two million deaths globally.Although,a new therapeutic molecule has not been developed for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)as of yet.As a result,some medications that had been previously authorized for use against SARS-CoV-2 could now be given to COVID-19 patients.The use of medications to treat COVID-19 is discussed in this publication.The report also discusses the lessons learned when using combination therapy,convalescent plasma therapy,immunotherapeutic molecules,and therapeutic molecules to treat COVID-19 patients.Several beneficial outcomes were noted with anti-viral therapy and immunotherapy.The COVID-19 medicine and vaccination have undergone 9,037 clinical trials since July 2022.It may be possible to provide COVID-19 patients with a successful outcome through the short-term repurposing of an existing drug.The evaluation of potential antiviral molecules can thus lead to more clinical trials being initiated.

Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent

Chemotherapy-induced complications,particularly lethal cardiovascular diseases,pose significant challenges for cancer survivors.The intertwined adverse effects,brought by cancer and its complication,further complicate anticancer therapy and lead to diminished clinical outcomes.Simple supplementation of cardioprotective agents falls short in addressing these challenges.Developing bifunctional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously.Drug repurposing was naturally endowed with co-therapeutic potential of two indications,implying a unique chance in the development of bi-functional agents.Herein,we further proposed a novel“trilogy of drug repurposing”strategy that comprises function-based,targetfocused,and scaffold-driven repurposing approaches,aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent.Through function-based repurposing,a cardioprotective agent,carvedilol(CAR),was identified as a potential neddylation inhibitor to suppress lung cancer growth.Employing target-focused SAR studies and scaffold-driven drug design,we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection.Remarkably,optimal derivative 43 displayed promising bi-functional effects,especially in various self-established heart failure mice models with and without tumor-bearing.Collectively,the present study validated the practicability of the“trilogy of drug repurposing”strategy in the development of bi-functional cotherapy agents.

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria

Sodium-glucose cotransporter 2(SGLT2)inhibitors have been reapproved for heart failure(HF)therapy in patients with and without diabetes.However,the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice.A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect.To address this issue,we conducted structural repurposing of EMPA,a representative SGLT2 inhibitor,to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2.Compared to EMPA,the optimal derivative JX01,which was produced by methylation of C2—OH of the glucose ring,exhibited weaker SGLT2-inhibitory activity(IC_(50)>100 nmol/L),and lower glycosuria and glucose-lowering side-effect,better NHE1-inhibitory activity and cardioprotective effect in HF mice.Furthermore,JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity,and good pharmacokinetic properties in both mouse and rat species.Collectively,the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs,and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Drug Repurposing for the Treatment of Mycobacterium abscessus Infections

With the ever-increasing burden of antimicrobial resistance,the demand to introduce countermeasures becomes increasingly critical.The urgency of this need is intensified by the void in antibiotic discovery,with the identification of novel compounds declining with time.Of increasing concern is Mycobacterium abscessus,which displays high levels of intrinsic resistance that lead to poor success rates,even after lengthy drug regimens.Research tackling these issues is now focused on the repurposing of preexisting drugs for antimycobacterial use,facilitating the discovery of antimicrobial compounds amidst a crisis where novel antibiotics are sparse.Part of this includes the use of combination treatments,whereby coadministration of synergistic compounds can reduce dose requirements and slow the progression of antimicrobial resistance in the long term.In this review,we will introduce the current therapeutic options for M.abscessus and provide insight into why treatment is so burdensome.We will also compile the current updates within drug repurposing for this pathogen,including the use of unconventional agents such as antimalarial drugs,the repositioning of antitubercu-losis candidates and the repurposing of preexisting antibiotics,including the application of combination regimens.In addition,the in vitro drug screening platforms used in their discovery will be appraised,with the view of highlighting potential future perspectives that may help increase physiological relevance.This review provides a timely appraisal of the future of M.abscessus treatment.

In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy

Objective:To select potential molecules that can target viral spike proteins,which may potentially interrupt the interaction between the human angiotension-converting enzyme 2(ACE2)receptor and viral spike protein by virtual screening.Methods:The three-dimensional(3D)-coordinate file of the receptor-binding domain(RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared.Secondly,approximately 15,000 molecular candidates were prepared,including US Food and Drug Administration(FDA)-approved drngs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology(TCMSP),for the docking process.Then,virtual screening was performed and the binding energy in Autodock Vina was calculated.Finally,the top 20 molecules with high binding energy and their Chinese medicine(CM)herb sources were listed in this paper.Results:It was found that digitoxin,a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores.Interestingly,two of the CM herbs containing the natural compounds that had relatively high binding scores,Forsyfh/ae frucft/s and/saf/d/s racWx,are components of Lianhua Qingwen(莲花清痕),a CM formula reportedly exerting activity against severe acute respiratory syndrome(SARS)-Cov-2.Moreover,raltegravir,an HIV integrase inhibitor,was found to have a relatively high binding score.Conclusions:A class of compounds,which are from FDA-approved drugs and CM natural compounds,that had high binding energy with RBD of the viral spike protein.Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection,and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.

Discovery and repurposing of artemisinin

Malaria is an ancient infectious disease that threatens millions of lives globally even today.The discovery of artemisinin,inspired by traditional Chinese medicine(TCM),has brought in a paradigm shift and been recognized as the“best hope for the treatment of malaria”by World Health Organization.With its high potency and low toxicity,the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries,including China,to eventually eradicate malaria.Here,we will first review the initial discovery of artemisinin,an extraordinary journey that was in stark contrast with many drugs in western medicine.We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer,inflammation,immunoregulation-related diseases,and COVID-19.Finally,we will discuss the implications of the“artemisinin story”and how that can better guide the development of TCM today.We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.

Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

Drug repurposing or repositioning has been well-known to refer to the therapeutic applications of a drug for another indication other than it was originally approved for.Repurposing non-oncology small-molecule drugs has been increasingly becoming an attractive approach to improve cancer therapy,with potentially lower overall costs and shorter timelines.Several non-oncology drugs approved by FDA have been recently reported to treat different types of human cancers,with the aid of some new emerging technologies,such as omics sequencing and artificial intelligence to overcome the bottleneck of drug repurposing.Therefore,in this review,we focus on summarizing the therapeutic potential of non-oncology drugs,including cardiovascular drugs,microbiological drugs,small-molecule antibiotics,anti-viral drugs,anti-inflammatory drugs,antineurodegenerative drugs,antipsychotic drugs,antidepressants,and other drugs in human cancers.We also discuss their novel potential targets and relevant signaling pathways of these old non-oncology drugs in cancer therapies.Taken together,these inspiring findings will shed new light on repurposing more non-oncology small-molecule drugs with their intricate molecular mechanisms for future cancer drug discovery.

Repurposing of antitumor drug candidate Quisinostat lead to novel spirocyclic antimalarial agents

Antimalarial chemotherapies endowed with effectiveness against drug-resistant parasites and good safety are urgently required in clinical.Our previous research revealed that clinical phaseⅡantitumor drug Quisinostat was a promising antimalarial prototype by inhibiting the activity of Plasmodium falciparum(P.falciparum)histone deacetylase(PfHDAC).Herein,30 novel spirocyclic linker derivatives were designed and synthesized based on Quisinostat as lead compound,and then their antimalarial activities and cytotoxicity were systematically evaluated.Among them,compounds 8 and 27 could effectively eliminate wild-type and multi-drug resistant P.falciparum parasites,and display weakened cytotoxicity and good metabolic stability.Western blot assay demonstrated that they could inhibit PfHDAC activity like Quisinostat.In addition,both 8 and 27 showed certain antimalarial efficacy in rodent malaria model,and the animal toxicity of 8 was significantly improved compared with Quisinostat.Overall,8 and 27 were structurally novel PfHDAC inhibitors and provided prospective prototype for further antimalarial drug research.

Repurposing clinical drugs is a promising strategy to discover drugs against Zika virus infection

Zika virus(ZIKV)is an emerging pathogen associated with neurological complications,such as Guillain–Barrésyndrome in adults and microcephaly in fetuses and newborns.This mosquito-borne flavivirus causes important social and sanitary problems owing to its rapid dissemination.However,the development of antivirals against ZIKV is lagging.Although various strategies have been used to study anti-ZIKV agents,approved drugs or vaccines for the treatment(or prevention)of ZIKV infections are currently unavailable.Repurposing clinically approved drugs could be an effective approach to quickly respond to an emergency outbreak of ZIKV infections.The well-established safety profiles and optimal dosage of these clinically approved drugs could provide an economical,safe,and efficacious approach to address ZIKV infections.This review focuses on the recent research and development of agents against ZIKV infection by repurposing clinical drugs.Their characteristics,targets,and potential use in anti-ZIKV therapy are presented.This review provides an update and some successful strategies in the search for anti-ZIKV agents are given.

Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of the most lethal malignant tumours worldwide.The mortality-to-incidence ratio is up to 91.6%in many countries,representing the third leading cause of cancer-related deaths.Systemic drugs,including the multikinase inhibitors sorafenib and lenvatinib,are first-line drugs used in HCC treatment.Unfortunately,these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance.Thus,novel pharmacological alternatives are urgently needed.For instance,immune checkpoint inhibitors have provided new approaches targeting cells of the immune system.Furthermore,monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients.In addition,drug combinations,including first-line treatment and immunotherapy,as well as drug repurposing,are promising novel therapeutic alternatives.Here,we review the current and novel pharmacological approaches to fight HCC.Preclinical studies,as well as approved and ongoing clinical trials for liver cancer treatment,are discussed.The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

γ-aminobutyric acid B2 receptor:A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus

BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying mechanisms.Previous studies showed thatγ-aminobutyric acid(GABA)B2 receptor(GABBR2)was upregulated in CCA cells cultured in high glucose(HG)conditions.Roles of GABA receptors in CCA progression have also been studied,but their association with DM and hyperglycemia in CCA remains unclarified.AIM To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.METHODS CCA cells,KKU-055 and KKU-213A,were cultured in Dulbecco Modified Eagle’s Medium supplemented with 5.6 mmol/L(normal glucose,NG)or 25 mmol/L(HG)glucose and assigned as NG and HG cells,respectively.GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot.Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence.GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry,and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis.Effects of baclofen,a GABA-B receptor agonist,on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays.Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment,and the candidate signaling molecules were validated using the public transcriptomic data and western blot.RESULTS GABBR2 expression in CCA cells was induced by HG in a dose-and time-dependent manner.CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia(P<0.01).High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors(P<0.05).HG cells of both tested CCA cell lines were more sensitive to baclofen treatment.Baclofen significantly suppressed the proliferation and clonogenicity of CCA cells in both NG and HG conditions(P<0.05).Phospho-kinase arrays suggested glycogen synthase kinase 3(GSK3),β-catenin,and the signal transducer and activator of transcription 3(STAT3)as candidate signaling molecules under the regulation of GABBR2,which were verified in NG and HG cells of the individual CCA cell lines.Cyclin D1 and c-Myc,the common downstream targets of GSK3/β-catenin and STAT3 involving cell proliferation,were accordingly downregulated after baclofen treatment.CONCLUSION GABBR2 is upregulated by HG and holds a promising role as a therapeutic target for CCA regardless of the glucose condition.

Applications and prospects of cryo-EM in drug discovery

Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition

Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.