{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:27Z","timestamp":1787028567984,"version":"build-2736575974"},"reference-count":154,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research (MIUR)","award":["PRIN 2022AT7P9T"],"award-info":[{"award-number":["PRIN 2022AT7P9T"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The transsulfuration pathway plays a central role in the regulation of sulfur metabolism and contributes to the maintenance of cellular homeostasis. Starting from homocysteine, a sulfur-containing amino acid derived from methionine via the methionine cycle, this metabolic pathway supports the biosynthesis of cysteine and other downstream products, such as taurine, serine, reduced glutathione and the gasotransmitter hydrogen sulfide (H2S). The most common disruption of this pathway leads to hyperhomocysteinemia (HHcy), a well-known risk factor for the development of cardiometabolic diseases and other pathological conditions. In this context, identifying effective pharmacological strategies is crucial. Based on both preclinical and clinical evidence, this review provides an updated overview on the role of folates in restoring transsulfuration balance in HHcy and explores the potential effects of downstream products (such as serine, taurine, and precursors of glutathione) under HHcy conditions. Finally, it examines the pharmacological properties of H2S-donors in cultured cells exposed to HHcy and in animal models of HHcy. This summary of the literature offers new perspectives for the treatment of HHcy and the prevention of its associated multiorgan complications.<\/jats:p>","DOI":"10.3390\/ijms26136430","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T09:57:39Z","timestamp":1751536659000},"page":"6430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Transsulfuration Pathway Products and H2S-Donors in Hyperhomocysteinemia: Potential Strategies Beyond Folic Acid"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7899-0954","authenticated-orcid":false,"given":"Lorenzo","family":"Flori","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0278-9446","authenticated-orcid":false,"given":"Sara","family":"Veneziano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-7107","authenticated-orcid":false,"given":"Alma","family":"Martelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cNutraceuticals and Food for Health\u201d, University of Pisa, via Del Borghetto 80, 56124 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cBiology and Pathology of Ageing\u201d, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6558-3065","authenticated-orcid":false,"given":"Eugenia","family":"Piragine","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cNutraceuticals and Food for Health\u201d, University of Pisa, via Del Borghetto 80, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Calderone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cNutraceuticals and Food for Health\u201d, University of Pisa, via Del Borghetto 80, 56124 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cBiology and Pathology of Ageing\u201d, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/bph.14446","article-title":"Regulators of the transsulfuration pathway","volume":"176","author":"Sbodio","year":"2019","journal-title":"Br. 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