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Sorafenib is the first FDA-approved systemic therapy for advanced HCC. This study investigates the influence of IL-23R (rs7517847) and ATG-10 (rs10514231) genetic polymorphisms on Sorafenib response, survival outcomes, average tolerable dose, and adverse events. This prospective open-label cohort study included 100 HCC patients, assessing IL-23R and ATG-10 genotypes via real-time polymerase chain reaction (RT-PCR). Patient's responses were evaluated using modified RECIST criteria. Statistical analyses evaluated the association of genetic variants with response, progression-free survival (PFS), overall survival (OS), average tolerable Sorafenib dose, and adverse events. IL-23R TT carriers had the highest Sorafenib response rate (80%) compared to GT (13.3%) and GG (6.7%) (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.021), while ATG-10 TT carriers had a 13.9-fold increased response likelihood (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.001). The T allele in ATG-10 significantly predicted longer PFS (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.025) and OS (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.011), suggesting a potential prognostic role. IL-23R GG carriers received significantly higher Sorafenib doses than TT (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0174) and GT (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0227), whereas ATG-10 had no effect on dosage. However, its CT genotype was significantly associated with a higher risk of Hand\u2013Foot Syndrome (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.012), and independent of dose (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0018). IL-23R and ATG-10 polymorphisms influence Sorafenib response, survival, and tolerability in HCC patients. Genetic screening may improve personalized treatment strategies by optimizing Sorafenib efficacy and minimizing toxicity.\n                  <\/jats:p>\n                  <jats:p>This trial was registered on clinicaltrials.gov with registration number NCT06030895, registered on \u201cSeptember 11th, 2023,\u201d retrospectively.<\/jats:p>","DOI":"10.1007\/s10238-025-01576-4","type":"journal-article","created":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T03:36:41Z","timestamp":1738985801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacogenomic insights: IL-23R and ATG-10 polymorphisms in Sorafenib response for hepatocellular carcinoma"],"prefix":"10.1007","volume":"25","clinical-trial-number":[{"clinical-trial-number":"nct06030895","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3039-5416","authenticated-orcid":false,"given":"Asmaa M.","family":"El-Sheshtawy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5983-3993","authenticated-orcid":false,"given":"Rehab H.","family":"Werida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7023-2454","authenticated-orcid":false,"given":"Monir Hussein","family":"Bahgat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5879-0557","authenticated-orcid":false,"given":"Shahira","family":"El-Etreby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9277-2910","authenticated-orcid":false,"given":"Noha A.","family":"El-Bassiouny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,8]]},"reference":[{"key":"1576_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s43046-020-0016-x","volume":"32","author":"WM Rashed","year":"2020","unstructured":"Rashed WM, Kandeil MAM, Mahmoud MO, Ezzat S. 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