{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T14:05:44Z","timestamp":1776693944983,"version":"3.51.2"},"reference-count":73,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Fondazione AIRC per la Ricerca sul Cancro (AIRC)","doi-asserted-by":"publisher","award":["IG 2019 ID 23825"],"award-info":[{"award-number":["IG 2019 ID 23825"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel\u2013Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1\u03b2, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein\u2013protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.<\/jats:p>","DOI":"10.3390\/genes15091167","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T02:34:06Z","timestamp":1725503646000},"page":"1167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In Silico Exploration of AHR-HIF Pathway Interplay: Implications for Therapeutic Targeting in ccRCC"],"prefix":"10.3390","volume":"15","author":[{"given":"Francesco","family":"Gregoris","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7013-5785","authenticated-orcid":false,"given":"Giovanni","family":"Minervini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4525-7793","authenticated-orcid":false,"given":"Silvio C. E.","family":"Tosatto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.plipres.2017.06.001","article-title":"Aryl Hydrocarbon Receptor (AHR): \u201cPioneer Member\u201d of the Basic-Helix\/Loop\/Helix per-Arnt-Sim (bHLH\/PAS) Family of \u201cSensors\u201d of Foreign and Endogenous Signals","volume":"67","author":"Nebert","year":"2017","journal-title":"Prog. Lipid Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kolonko-Adamska, M., Uversky, V.N., and Greb-Markiewicz, B. (2021). The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development. Int. J. Mol. 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