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Oral systemic therapies, including methotrexate, cyclosporine, acitretin, and apremilast, remain integral to psoriasis management, particularly for patients with moderate-to-severe disease who cannot afford biologic therapy. While these treatments are effective, their long-term use is often limited by adverse effects, particularly hepatotoxicity. Methotrexate and acitretin are associated with liver toxicity, requiring regular monitoring, whereas cyclosporine presents a lower but notable risk. Apremilast, a phosphodiesterase 4 inhibitor, offers a safer hepatic profile but has lower efficacy than traditional systemic agents. Emerging therapies, such as TYK2 inhibitors, ROR\u03b3t inhibitors, and novel PDE4 inhibitors, aim to improve treatment efficacy while minimizing adverse effects. Advances in understanding hepatotoxicity mechanisms have led to identifying predictive biomarkers and hepatoprotective strategies, including antioxidants and non-invasive imaging techniques. Personalized medicine approaches, including pharmacogenomics, are revolutionizing treatment selection by optimizing efficacy while minimizing toxicity risks. This comprehensive review examines oral psoriasis treatments\u2019 efficacy and hepatotoxicity profiles, discusses novel therapeutic developments, and explores strategies for mitigating liver-related adverse effects. A balanced approach that integrates clinical monitoring, lifestyle modifications, and emerging precision medicine techniques is essential for optimizing long-term treatment outcomes. Future research should focus on refining predictive models for drug-induced liver injury and developing targeted therapies with improved efficacy and safety profiles.\u00a0<\/jats:p>\n \n Graphical Abstract<\/jats:bold>\n <\/jats:p>\n \n Created in BioRender. Elgindy, A. (2025)\n https:\/\/BioRender.com\/vcab653<\/jats:ext-link>\n <\/jats:p>","DOI":"10.1007\/s00210-025-04334-1","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T04:51:09Z","timestamp":1750827069000},"page":"16355-16384","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Balancing efficacy and hepatotoxicity: a comprehensive review of oral medications in psoriasis management"],"prefix":"10.1007","volume":"398","author":[{"given":"Alaa E.","family":"Elsisi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally El-Sayed","family":"Abu-Risha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2871-2603","authenticated-orcid":false,"given":"Mahmoud Abdelrahman","family":"Alkabbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila A.","family":"Ramadan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samia Salem","family":"Sokar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"issue":"1","key":"4334_CR1","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1007\/s11033-024-09792-z","volume":"51","author":"N Abdallah","year":"2024","unstructured":"Abdallah N, Amer ME, Amer MA, El-Missiry MA, Othman AI (2024) Melatonin mitigated methotrexate-induced hepatotoxicity through interrelated biological processes. 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