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.