Mapping Hydrogen Sulfide Biosynthesis and Oxidation Pathways in Placental Health and Disease: a Scoping Review

Hydrogen sulfide (H₂S) plays an important role in placental function. Its bioavailability depends on the balance between enzymatic synthesis by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE/CTH) and 3-mercaptopyruvate sulfurtransferase (3-MST/MPST), and mitochondrial oxidation through sulfide:quinone oxidoreductase (SQOR), persulfide dioxygenase (ETHE1) and thiosulfate sulfurtransferase (TST). However, the extent to which H₂S synthesis, oxidation and experimental modulation have been investigated in placental systems remains unclear. This scoping review mapped the placental H₂S literature to identify where evidence is concentrated and where gaps remain. Following JBI methodology and PRISMA-ScR reporting, Scopus, Embase, MEDLINE and Web of Science were searched for primary studies involving placental or trophoblast H₂S biology. Sixty-four studies were included. Pre-eclampsia dominated the literature (n = 27), while most other pregnancy conditions were sparsely represented. CBS and CSE/CTH were investigated in 34 and 29 studies respectively, while 3-MST/MPST was investigated in only seven studies. None of the included studies assessed the principal mitochondrial sulfide-oxidation enzymes SQOR, ETHE1 or TST. Sulfide concentrations, relative assay signals or H₂S production were reported in 23 studies across six analytical approaches. Sulfide measurement was highly heterogeneous across studies, making direct comparison between studies limited. H₂S was experimentally modulated in 85 intervention applications but measured in only 23. Overall, placental H₂S research is concentrated on biosynthetic enzyme expression and pre-eclampsia, while sulfide clearance, early gestation and standardised measurement remain major gaps. These gaps limit interpretation of changes in placental H₂S bioavailability and the evaluation of donor-based therapeutic strategies.