Sesame (Sesamum indicum L.), is one of the earliest domesticated oilseed crops. It is valued for its exceptional oil content, bioactive compounds, and adaptability to diverse agroclimatic conditions. However, its production remains highly susceptible to water scarcity particularly terminal drought and intermittent moisture deficits that in turn severely compromise the yield and oil quality. Recent advances in genomics, transcriptomics, proteomics, metabolomics, epigenomics, and phenomics have placed sesame as an emerging model for multi-omics-driven stress research. These approaches have uncovered key regulators of drought (NAC, MYB, WRKY), protective proteins (late embryogenesis abundant proteins, heat shock proteins, antioxidant enzymes), osmolyte- and redox-related metabolites, and hormonal signalling modules such as PYL-SnRK2-ABF (ABA), LOX/AOS/OPR (jasmonate), and EIN/ERF (ethylene). Addressing these gaps will require investments in precision phenotyping, robust pan-genomic databases, functional validation using CRISPR/Cas9 tools, and global data-sharing networks. This review highlights the current advances in sesame drought research across omics platforms, critically evaluates their relevance to breeding programs, and offers the first comprehensive multi-omics perspective on moisture-stress adaptation in sesame. Additionally, KEGG pathway-guided multi-omics integration connects ABA signaling, phenylpropanoid metabolism, and antioxidant pathways to drought adaptation in sesame. By bridging mechanistic insights with applied strategies, it highlights pathways to accelerate the development of climate-resilient sesame cultivars.
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