Carolina M. Polonio, Kimberly A. McHale, David H. Sherr, David Rubenstein, Francisco J. Quintana
{"title":"The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation","authors":"Carolina M. Polonio, Kimberly A. McHale, David H. Sherr, David Rubenstein, Francisco J. Quintana","doi":"10.1038/s41573-025-01172-x","DOIUrl":"https://doi.org/10.1038/s41573-025-01172-x","url":null,"abstract":"<p>The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor originally identified as the target mediating the toxic effects of environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and dioxins. For years, AHR activation was actively avoided during drug development. However, the AHR was later identified as an important physiological regulator of the immune response. These findings triggered a paradigm shift that resulted in identification of the AHR as a regulator of both innate and adaptive immunity and outlined a pathway for its modulation by the diet, commensal flora and metabolism in the context of autoimmunity, cancer and infection. Moreover, the AHR was revealed as a candidate target for the therapeutic modulation of the immune response. Indeed, the first AHR-activating drug (tapinarof) was recently approved for the treatment of psoriasis. Clinical trials are underway to evaluate the effects of tapinarof and other AHR-targeting therapeutics in inflammatory diseases, cancer and infections. This Review outlines the molecular mechanism of AHR action, and describes how it regulates the immune response. We also discuss links to disease and AHR-targeting therapeutics that have been tested in past and ongoing clinical trials.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Back to the drawing board for anhedonia drugs","authors":"","doi":"10.1038/d41573-025-00073-3","DOIUrl":"https://doi.org/10.1038/d41573-025-00073-3","url":null,"abstract":"Johnson & Johnson has discontinued development of aticaprant for depression with anhedonia, a blow to hopes for drugs for ‘domains’ of psychiatric disorders.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Back to therapeutic modality basics","authors":"","doi":"10.1038/d41573-025-00072-4","DOIUrl":"https://doi.org/10.1038/d41573-025-00072-4","url":null,"abstract":"Andy Plump, Takeda’s head of R&D, discusses the company’s evolving pipeline, therapeutic modalities, and upheaval in biotech, the NIH and the FDA.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"FDA new drug approvals in Q1 2025","authors":"","doi":"10.1038/d41573-025-00071-5","DOIUrl":"https://doi.org/10.1038/d41573-025-00071-5","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Analysis of China-to-West pharmaceutical licensing deals in 2024","authors":"","doi":"10.1038/d41573-025-00068-0","DOIUrl":"https://doi.org/10.1038/d41573-025-00068-0","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel drug targets in 2024","authors":"","doi":"10.1038/d41573-025-00069-z","DOIUrl":"https://doi.org/10.1038/d41573-025-00069-z","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeffrey L. Cummings, Charlotte E. Teunissen, Brian K. Fiske, Isabelle Le Ber, Kristin R. Wildsmith, Michael Schöll, Billy Dunn, Philip Scheltens
{"title":"Biomarker-guided decision making in clinical drug development for neurodegenerative disorders","authors":"Jeffrey L. Cummings, Charlotte E. Teunissen, Brian K. Fiske, Isabelle Le Ber, Kristin R. Wildsmith, Michael Schöll, Billy Dunn, Philip Scheltens","doi":"10.1038/s41573-025-01165-w","DOIUrl":"https://doi.org/10.1038/s41573-025-01165-w","url":null,"abstract":"<p>Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"183 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Trends in the drug target landscape for autoimmune diseases","authors":"","doi":"10.1038/d41573-025-00061-7","DOIUrl":"https://doi.org/10.1038/d41573-025-00061-7","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"183 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"FDA approves siRNA drug for haemophilia prophylaxis","authors":"","doi":"10.1038/d41573-025-00066-2","DOIUrl":"https://doi.org/10.1038/d41573-025-00066-2","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"107 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oral IL-23-blocking peptide racks up phase III wins in inflammatory disease","authors":"","doi":"10.1038/d41573-025-00063-5","DOIUrl":"https://doi.org/10.1038/d41573-025-00063-5","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"103 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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