{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:54:35Z","timestamp":1792504475687,"version":"4.5.0"},"reference-count":43,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T00:00:00Z","timestamp":1655337600000},"content-version":"unspecified","delay-in-days":15,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,5,17]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:p>The Sonic hedgehog (Shh) signaling pathway is an essential pathway in the human body that plays an important role in embryogenesis and tissue homeostasis. Aberrant activation of this pathway has been linked to the development of different diseases, ranging from cancer to immune dysregulation and infections.<\/jats:p>\n               <jats:p>Uncontrolled activation of the pathway through sporadic mutations or other mechanisms is associated with cancer development and progression in various malignancies, such as basal cell carcinoma, medulloblastoma, pancreatic cancer, breast cancer and small-cell lung carcinoma. Targeted inhibition of the pathway components has therefore emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Currently, two main components of the pathway, the smoothened receptor and the glioma-associated oncogene homolog transcriptional factors, have been investigated for the development of targeted drugs, leading to the marketing authorization of three smoothened receptor inhibitors for the treatment of basal cell carcinoma and acute myeloid leukemia.<\/jats:p>\n               <jats:p>The Shh pathway also seems to be involved in regulating the immune response, possibly playing a role in immune system evasions by tumors, development of autoimmune diseases, such as rheumatoid arthritis and Crohn\u2019s disease, airway inflammation, and diseases related to aberrant activation of T-helper 2 cellular response, such as allergy, atopic dermatitis, and asthma.<\/jats:p>\n               <jats:p>Finally, the Shh pathway is involved in pathogen-mediated infection, including influenza-A and, more recently, SARS-CoV-2 viruses. Therefore, agents that inhibit the Shh signaling pathway might be used to treat pathogenic infections, shifting the therapeutic approach from strain-specific treatments to host-based strategies that target highly conserved host targets.<\/jats:p>","DOI":"10.1136\/jitc-2021-004397","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T11:05:51Z","timestamp":1655377551000},"page":"e004397","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Sonic hedgehog pathway for the treatment of inflammatory diseases: implications and opportunities for future research"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8901-0974","authenticated-orcid":false,"given":"Marco","family":"Palla","sequence":"first","affiliation":[{"name":"Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Scarpato","sequence":"additional","affiliation":[{"name":"Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Di Trolio","sequence":"additional","affiliation":[{"name":"Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8322-475X","authenticated-orcid":false,"given":"Paolo Antonio","family":"Ascierto","sequence":"additional","affiliation":[{"name":"Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"key":"2025100314281421000_10.6.e004397.1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3390\/jdb5040014","article-title":"The hedgehog signaling pathway emerges as a pathogenic target","volume":"5","author":"Smelkinson","year":"2017","journal-title":"J Dev Biol"},{"key":"2025100314281421000_10.6.e004397.2","doi-asserted-by":"crossref","DOI":"10.3390\/cancers8020022","article-title":"Targeting the sonic hedgehog signaling pathway: review of smoothened and Gli inhibitors","volume":"8","author":"Rimkus","year":"2016","journal-title":"Cancers"},{"key":"2025100314281421000_10.6.e004397.3","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s40264-018-0777-5","article-title":"Efficacy and safety of sonic hedgehog pathway inhibitors in cancer","volume":"42","author":"Carpenter","year":"2019","journal-title":"Drug Saf"},{"key":"2025100314281421000_10.6.e004397.4","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-019-0459-7"},{"key":"2025100314281421000_10.6.e004397.5","doi-asserted-by":"publisher","DOI":"10.17305\/bjbms.2018.2756"},{"key":"2025100314281421000_10.6.e004397.6","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3390\/cells8020153","article-title":"Targeting the hedgehog pathway in cancer: current evidence and future perspectives","volume":"8","author":"Girardi","year":"2019","journal-title":"Cells"},{"key":"2025100314281421000_10.6.e004397.7","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31724"},{"key":"2025100314281421000_10.6.e004397.8","doi-asserted-by":"crossref","DOI":"10.1007\/s11864-019-0683-9","article-title":"Sonic hedgehog pathway inhibition in the treatment of advanced basal cell carcinoma","volume":"20","author":"Leavitt","year":"2019","journal-title":"Curr Treat Options Oncol"},{"key":"2025100314281421000_10.6.e004397.9","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028175"},{"key":"2025100314281421000_10.6.e004397.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3598"},{"key":"2025100314281421000_10.6.e004397.11","doi-asserted-by":"publisher","DOI":"10.1242\/dev.083691"},{"key":"2025100314281421000_10.6.e004397.12","doi-asserted-by":"publisher","DOI":"10.1242\/dev.120154"},{"key":"2025100314281421000_10.6.e004397.13","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1111\/jdv.16230","article-title":"Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma: a joint expert opinion","volume":"34","author":"Dummer","year":"2020","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"2025100314281421000_10.6.e004397.14","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.142"},{"key":"2025100314281421000_10.6.e004397.15","article-title":"Hedgehog pathway inhibitors as targeted cancer therapy and strategies to overcome drug resistance","volume":"23","author":"Nguyen","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025100314281421000_10.6.e004397.16","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b06087"},{"key":"2025100314281421000_10.6.e004397.17","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3389\/fchem.2020.00498","article-title":"Discovery of small molecule inhibitors targeting the sonic hedgehog","volume":"8","author":"Yun","year":"2020","journal-title":"Front Chem"},{"key":"2025100314281421000_10.6.e004397.18","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.737245","article-title":"Systemic pharmacological smoothened inhibition reduces lung T-cell infiltration and ameliorates Th2 inflammation in a mouse model of allergic airway disease","volume":"12","author":"Y\u00e1nez","year":"2021","journal-title":"Front Immunol"},{"key":"2025100314281421000_10.6.e004397.19","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.jaci.2019.07.011","article-title":"Hedgehog signaling promotes T\n                  H\n               2 differentiation in naive human CD4 T cells","volume":"144","author":"Y\u00e1nez","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"2025100314281421000_10.6.e004397.20","article-title":"Sonic hedgehog signalling in the regulation of barrier tissue homeostasis and inflammation","author":"Lau","year":"2021","journal-title":"Febs J"},{"key":"2025100314281421000_10.6.e004397.21","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6765"},{"key":"2025100314281421000_10.6.e004397.22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.438846"},{"key":"2025100314281421000_10.6.e004397.23","doi-asserted-by":"crossref","DOI":"10.3390\/cells7120272","article-title":"Targeting the oncoprotein smoothened by small molecules: focus on novel acylguanidine derivatives as potent smoothened inhibitors","volume":"7","author":"Pietrobono","year":"2018","journal-title":"Cells"},{"key":"2025100314281421000_10.6.e004397.24","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3390\/cells8050394","article-title":"Recent advances in the clinical targeting of Hedgehog\/GLI signaling in cancer","volume":"8","author":"Xie","year":"2019","journal-title":"Cells"},{"key":"2025100314281421000_10.6.e004397.25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028077"},{"key":"2025100314281421000_10.6.e004397.26","doi-asserted-by":"publisher","DOI":"10.1038\/nature07275"},{"key":"2025100314281421000_10.6.e004397.27","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2824"},{"key":"2025100314281421000_10.6.e004397.28","doi-asserted-by":"crossref","first-page":"e339","DOI":"10.1016\/S2352-3026(15)00096-4","article-title":"Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study","volume":"2","author":"Martinelli","year":"2015","journal-title":"Lancet Haematol"},{"key":"2025100314281421000_10.6.e004397.29","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-0365"},{"key":"2025100314281421000_10.6.e004397.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616447113"},{"key":"2025100314281421000_10.6.e004397.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1244689"},{"key":"2025100314281421000_10.6.e004397.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006588"},{"key":"2025100314281421000_10.6.e004397.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.03.03"},{"key":"2025100314281421000_10.6.e004397.34","doi-asserted-by":"crossref","DOI":"10.3390\/v12050525","article-title":"Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2\u2019-O-Methylation of Viral RNA","volume":"12","author":"Encinar","year":"2020","journal-title":"Viruses"},{"key":"2025100314281421000_10.6.e004397.35","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2026131"},{"key":"2025100314281421000_10.6.e004397.36","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.825749"},{"key":"2025100314281421000_10.6.e004397.37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.570993"},{"key":"2025100314281421000_10.6.e004397.38","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(20)30127-2"},{"key":"2025100314281421000_10.6.e004397.39","doi-asserted-by":"crossref","first-page":"e253","DOI":"10.1016\/S2665-9913(21)00012-6","article-title":"Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study","volume":"3","author":"Cavalli","year":"2021","journal-title":"Lancet Rheumatol"},{"key":"2025100314281421000_10.6.e004397.40","doi-asserted-by":"publisher","DOI":"10.1038\/nri2151"},{"key":"2025100314281421000_10.6.e004397.41","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12379"},{"key":"2025100314281421000_10.6.e004397.42","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s10238-016-0434-1","article-title":"Disruption of the hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation","volume":"17","author":"Buongusto","year":"2017","journal-title":"Clin Exp Med"},{"key":"2025100314281421000_10.6.e004397.43","first-page":"8557","article-title":"Hedgehog signaling regulates the expression levels of inflammatory mediators in cigarette\u2011induced airway inflammation","volume":"17","author":"Guo","year":"2018","journal-title":"Mol Med Rep"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2021-004397","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T21:28:24Z","timestamp":1759526904000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2021-004397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6,16]]},"published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1136\/jitc-2021-004397"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2021-004397","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6]]}}}