Background　The　involvement　of　mitochondrial　and　programmed　cell　death　(mtPCD)-related　genes　in　the　pathogenesis　of　pre-eclampsia　(PE)　remains　inadequately　characterized.Methods　This　study　explores　the　role　of　mtPCD　genes　in　PE　through　bioinformatics　and　experimental　approaches.　Differentially　expressed　mtPCD　genes　were　identified　as　potential　biomarkers　from　the　GSE10588　and　GSE98224　datasets　and　subsequently　validated.　Hub　genes　were　determined　using　support　vector　machine,　least　absolute　shrinkage　and　selection　operator,　and　Boruta　based　on　consistent　expression　profiles.　Their　performance　was　assessed　through　nomogram　and　artificial　neural　network　models.　Biomarkers　were　subjected　to　localization,　functional　annotation,　regulatory　network　analysis,　and　drug　prediction.　Clinical　validation　was　conducted　via　real-time　quantitative　polymerase　chain　reaction　(RT-qPCR),　immunofluorescence,　and　Western　blot.Results　Four　genes　[solute　carrier　family　25　member　5　(SLC25A5),　acyl-CoA　synthetase　family　member　2　(ACSF2),　mitochondrial　fission　factor　(MFF),　and　phorbol-12-myristate-13-acetate-induced　protein　1　(PMAIP1)]　were　identified　as　biomarkers　distinguishing　PE　from　normal　controls.　Functional　analysis　indicated　their　involvement　in　various　biological　pathways.　Immune　analysis　revealed　associations　between　biomarkers　and　immune　cell　activity.　A　regulatory　network　was　informed　by　biomarker　expression　and　database　predictions,　in　which　KCNQ1OT1　modulates　ACSF2　expression　via　hsa-miR-200b-3p.　Drug　predictions,　including　clodronic　acid,　were　also　proposed.　Immunofluorescence,　RT-qPCR,　and　Western　blot　confirmed　reduced　expression　of　SLC25A5,　MFF,　and　PMAIP1　in　PE,　whereas　ACSF2　was　significantly　upregulated.Conclusion　These　four　mtPCD-related　biomarkers　may　play　a　pivotal　role　in　PE　pathogenesis,　offering　new　perspectives　on　the　disease＇s　diagnostic　and　mechanistic　pathways.