{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:13:03Z","timestamp":1788959583870,"version":"build-2803163510"},"reference-count":0,"publisher":"Cambridge University Press (CUP)","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"unspecified","delay-in-days":215,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Expert Rev. Mol. Med."],"published-print":{"date-parts":[[2026]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n The sphingolipid rheostat \u2013 the interconversion between pro-apoptotic ceramide (Cer) and pro-survival sphingosine-1-phosphate (S1P) \u2013 governs female reproductive homeostasis. This review integrates mechanistic evidence across the reproductive continuum to elucidate how compartmentalised disruptions of this axis drive divergent pathologies.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A systematic search up to 2026 across PubMed and Web of Science identified molecular mechanisms and translational models linking sphingolipid signalling to ovarian ageing, polycystic ovary syndrome (PCOS), endometriosis, adenomyosis and uterine fibroids.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Pathological Cer accumulation drives mitochondrial outer membrane permeabilisation (MOMP) and cytochrome c release, accelerating follicular atresia in primary ovarian insufficiency (POI). Conversely, PCOS is associated with heterogeneous remodeling of follicular-fluid sphingolipids, compromising oocyte competence. Within uterine and peritoneal microenvironments, a hyper-activated S1P axis operating via S1PR1\u20133 networks acts as a core pathogenic engine. This axis exhibits a threshold-dependent dual nature: low thresholds promote homeostatic survival, whereas high thresholds drive M2 macrophage polarisation for immune evasion and cross-link with TGF-\u03b2\/Smad and Activin A cascades to stimulate fibroblast-to-myofibroblast transdifferentiation (FMT) and extracellular matrix deposition in endometriosis and fibroids. Additionally, the SphK\/S1P axis amplifies chronic pelvic pain by modulating nerve growth factor (NGF) and transient receptor potential vanilloid 4 channels.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n The sphingolipid axis constitutes a unifying molecular rheostat in reproductive medicine. Mapping these compartmentalised lipidomic signatures enables high-resolution diagnostics, while targeted sub-receptor antagonists and non-hormonal drug repurposing offer promising, fertility-preserving therapeutic frontiers. However, successfully translating these lipid-targeted interventions into clinical practice demands addressing key bottlenecks regarding systemic off-target toxicities and engineering advanced, tissue-specific delivery platforms.<\/jats:p>\n <\/jats:sec>","DOI":"10.1017\/erm.2026.10070","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:38:49Z","timestamp":1785836329000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":0,"title":["The Sphingolipid Rheostat in Female Reproductive Pathologies: From Molecular Mechanisms to Precision Therapeutics"],"prefix":"10.1017","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3763-7537","authenticated-orcid":false,"given":"Ruolin","family":"Mao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04xy45965","id-type":"ROR","asserted-by":"publisher"}],"name":"Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0367-7765","authenticated-orcid":false,"given":"Lei","family":"Jin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04xy45965","id-type":"ROR","asserted-by":"publisher"}],"name":"Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1430-4336","authenticated-orcid":false,"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04xy45965","id-type":"ROR","asserted-by":"publisher"}],"name":"Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2026,8,4]]},"container-title":["Expert Reviews in Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S1462399426100702","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:05:41Z","timestamp":1788959141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S1462399426100702\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":0,"alternative-id":["S1462399426100702"],"URL":"https:\/\/doi.org\/10.1017\/erm.2026.10070","relation":{},"ISSN":["1462-3994"],"issn-type":[{"value":"1462-3994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026]]},"assertion":[{"value":"\u00a9 The Author(s), 2026. Published by Cambridge University Press","name":"copyright","label":"Copyright","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http:\/\/creativecommons.org\/licenses\/by\/4.0), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.","name":"license","label":"License","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}],"article-number":"e40"}}