Editorial: "Unraveling the Mechanisms of Bioactive Molecules: The Pivotal Role of Omics Technology"

Linhui Zhai^1*Bingbing Hao^2*Eric B Dammer^3*Zhongwei Xu^4*

• ¹School of Medicine, Tongji University, Shanghai, China
• ²Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, China
• ³Emory University Department of Cell Biology, Atlanta, United States
• ⁴Logistics University of of People's Armed Police Force, Tianjin, China

This Frontiers Research Topic aims to emphasize the role of omics technologies in elucidating the mechanisms of bioactive molecules. Bioactive molecules-ranging from plant-derived phytochemicals and microbial metabolites to endogenous peptides and synthetic small moleculeshold immense potential for advancing human health, agriculture, and environmental sustainability. However, their full therapeutic and functional potential remains largely unrealized due to the complexity of their mechanisms of action. These molecules often engage multiple biological targets, modulate interconnected signaling pathways, and produce context-dependent effects that vary across cell types and organisms. For decades, conventional experimental approaches-such as single-target assays and candidate-gene studies-have yielded only fragmented insights into these complex interactions (Hopkins 2008), thereby constraining efforts to rationally optimize bioactive molecules for applications in medicine, crop protection, and bioremediation. In recent years, the emergence of omics technologies-high-throughput methodologies that enable comprehensive profiling of genomes, transcriptomes, proteomes, metabolomes, and other molecular layers-has profoundly transformed this field. By capturing system-wide biological responses to bioactive compounds, omics approaches effectively bridge the gap between observed phenotypic outcomes and their underlying molecular mechanisms, thereby advancing mechanism-driven research into new frontiers.The study of bioactive molecules has traditionally relied on a reductionist approach-identifying a single molecular target, such as a receptor or enzyme, and examining how a compound binds to or inhibits it. However, this paradigm fails to capture the broader "network effect" exhibited by bioactive molecules. For instance, plant polyphenols like resveratrol do not act exclusively on sirtuins. They modulate hundreds of proteins, alter metabolite profiles, and reprogram gene expression networks associated with inflammation, oxidative stress, and aging.Omics technologies overcome this limitation by offering a comprehensive, system-level perspective on biological changes (Yan, Liu et al. 2015). Transcriptomics, for example, can uncover how a bioactive compound reprograms gene expression in specific cell lines or tissues, thereby revealing previously unrecognized functional pathways. Proteomics complements these insights by detecting post-translational modifications-such as phosphorylation and acetylation-that modulate protein activity, while metabolomics captures dynamic alterations in small-molecule metabolites, providing a direct measure of biochemical pathway disruption. Collectively, these approaches convert isolated observations into robust, data-driven hypotheses regarding molecular mechanisms.A recent study on curcumin, a polyphenol with anti-inflammatory properties, used integrative multiomics-combining transcriptomic, proteomic, and metabolomic data from human immune cellsto identify NF-κB, a key inflammatory transcription factor, as central to curcumin's action (El-Saadony, Saad et al. 2025). Experiments showed that curcumin inhibits NF-κB by stabilizing its inhibitor, IκBα, demonstrating how multi-omics turns big data into actionable mechanistic insights. Multi-omics has also clarified the mechanisms of traditional Chinese medicine (TCM) compounds, which often act on multiple targets. For example, puerarin, a flavonoid from Pueraria lobata, was found to directly bind the GABAA receptor α1 subunit (GABRA1) using photoaffinity chemical proteomics (Liu, Jiang et al. 2024). Cryo-EM revealed the binding site, showing that puerarin inhibits dorsal motor nucleus (DMV) neurons and reduces intestinal fat absorption, supporting its anti-obesity potential. Similarly, artemisinin, a sesquiterpene lactone with antimalarial activity, was shown via immunoprecipitation-mass spectrometry (IP-MS) to target LONP1 (lon protease 1) (Jeon, Lee et al. 2020). By enhancing the LONP1-CYP11A1 interaction, artemisinin reduces ovarian androgen synthesis, offering a new therapy for polycystic ovary syndrome (PCOS). These studies illustrate how omics advances our understanding of molecular mechanisms. Our frontiers research topic this special issue presents recent advances in the mechanistic research of various active molecules utilizing omics technologies, encompassing the following relevant topics.Liquiritigenin is a planar dihydroflavonone monomer with strong anti-inflammatory activity. Ping Liu et al. Despite its significant technological advantages, omics-driven mechanistic research faces several challenges. First, data quality and standardization remain major challenges: differences in sample preparation, sequencing platforms, and analysis pipelines affect reproducibility. Second, omics findings require rigorous validation, as high-throughput methods often yield false positives; mechanistic hypotheses must be confirmed with targeted low-throughput experiments-such as CRISPR knockout or in vitro binding assays. Third, the high cost and limited access to omics technologies restrict their use in low-resource settings, where many bioactive compounds, including those from traditional medicinal plants, are found. Lowering sequencing and metabolomics costs and strengthening capacity-building are essential to closing this gap.Looking ahead, several key trends are poised to shape the future of this field. Single-cell omics will allow researchers to investigate the mechanisms of bioactive molecules at the cellular level, revealing differential responses among distinct cell types within a tissue to the same molecule. Spatial omics, which maps molecular alterations across tissue sections, will further enhance our understanding of context-dependent effects-for instance, how chemotherapeutics selectively target tumor cells while sparing adjacent healthy tissues. Moreover, multi-species omics will provide insights into inter-organismal interactions, such as how metabolites produced by gut microbiota influence host physiology or how plant-derived compounds affect insect pests. The next generation of omics technologies is expected to address current limitations. For example, peptide-centric local stability assay (PELSA) (Li, Chen et al. 2025) and limited proteolysis coupled with mass spectrometry (LiP-MS) (Feng, De Franceschi et al. 2014) enable label-free identification of molecular targets by detecting ligand-induced protein conformational changes, eliminating the need for probe design and thereby extending its utility to non-covalent binders. The study of bioactive molecule mechanisms has entered a new era thanks to omics technology. Researchers can now move beyond single targets or isolated pathways to explore the full complexity of biological systems, revealing hidden interactions and context-dependent effects. By integrating multi-omics data with advanced computational tools, scientists are turning big data into actionable insights that accelerate translation from bench to bedside, field, and environment. However, challenges related to standardization and accessibility persist, necessitating coordinated efforts across the scientific community. As these technologies advance, omics approaches will enhance our understanding of bioactive molecules and enable their potential to address critical global issuessuch as disease, food security, and environmental degradation. They are poised to fully realize the therapeutic potential of bioactive compounds, thereby accelerating the development of precision medicine.