In this perspective, we discuss the current challenges and opportunities in multi-omics, a rapidly evolving approach that integrates multiple molecular layers to advance our understanding of complex biological systems. As biomedical research moves toward precision medicine, the ability to correlate genotype, phenotype, and environmental contexts has never been more critical. Multi-omics enhances biomarker discovery and elucidates regulatory networks underlying health and disease. The dominant scientific paradigm for over a century was to take a reductionist approach, studying individual molecular components in isolation or as simplified systems. The advent of omics technologies in the 1990s enabled a systems paradigm, allowing holistic analyses of molecular networks. These early systems studies were constrained by technology and methodology to bulk tissue measurements and single-omics analyses. Recent advances in single-cell and spatial omics, high-throughput proteomics and metabolomics, cloud computing, and artificial intelligence now allow high-resolution, spatially contextualized multi-omics analyses. Despite these gains, challenges in data analysis and interpretation remain, including high dimensionality, missing or incomplete data, multiple batch effects, and method-specific variability. Emerging strategies—such as paired data collection, staged or joint integration, and latent factor or quasi-mediation frameworks—offer promising solutions, positioning multi-omics as a transformative tool for elucidating complex mechanisms and guiding personalized medicine. Continued refinement of these approaches may further enhance the utility of multi-omics for understanding complex biological systems.

The replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its main protease (M^pro), which is a plausible therapeutic target for coronavirus disease 2019 (COVID-19). Although numerous in silico studies reported the potential inhibitory effects of natural products including cannabis and cannabinoids on SARS-CoV-2 M^pro, their anti-M^pro activities are not well validated by biological experimental data. Herein, a library of minor cannabinoids belonging to several chemotypes including tetrahydrocannabinols, cannabidiols, cannabigerols, cannabichromenes, cannabinodiols, cannabicyclols, cannabinols, and cannabitriols was evaluated for their anti-M^pro activity using a biochemical assay. Additionally, the binding affinities and molecular interactions between the active cannabinoids and the M^pro protein were studied by a biophysical technique (surface plasmon resonance; SPR) and molecular docking, respectively. Cannabinoids tetrahydrocannabutol and cannabigerolic acid were the most active M^pro inhibitors (IC₅₀ = 3.62 and 14.40 μM, respectively) and cannabigerolic acid had a binding affinity $K_D=2.16\times {10}^{-4}$ M). A preliminary structure and activity relationship study revealed that the anti-${\mathrm{M}}^{\mathrm{pro}}$ effects of cannabinoids were influenced by the decarboxylation of cannabinoids and the length of cannabinoids’ alkyl side chain. Findings from the biochemical, biophysical, and computational assays support the growing evidence of cannabinoids’ inhibitory effects on SARS-CoV-2 M^pro.

Tyrosinase (TYR) plays a key role in the enzymatic reaction that is responsible for a range of unwanted discoloration effects, such as food browning and skin hyperpigmentation. TYR inhibitors could, therefore, be candidates for skin care products that aim to repair pigmentation problems. In this study, we used a metabolomics approach combined with the isobologram analysis to identify anti-TYR compounds within natural resources, and evaluate their possible synergism with each other. Rheum palmatum was determined to be a model plant for observing the effect, of which seven extracts with diverse phytochemicals were prepared by way of pressurized solvent extraction. Each Rheum palmatum extract (RPE) was profiled using nuclear magnetic resonance spectroscopy and its activity of tyrosinase inhibition was evaluated. According to the orthogonal partial least square analysis used to correlate phytochemicals in RPE with the corresponding activity, the goodness of fit of the model (R₂ = 0.838) and its predictive ability (Q₂ = 0.711) were high. Gallic acid and catechin were identified as the active compounds most relevant to the anti-TYR effect of RPE. Subsequently, the activity of gallic acid and catechin were evaluated individually, and when combined in various ratios by using isobologram analysis. The results showed that gallic acid and catechin in the molar ratios of 9:5 and 9:1 exhibited a synergistic inhibition on TYR, with a combination index lower than 0.77, suggesting that certain combinations of these compounds may prove effective for use in cosmetic, pharmaceutical, and food industries.

Bulky organic carcinogens are activated in vivo and subsequently react with nucleobases of cellular DNA to produce adducts. Some of these DNA adducts exist in multiple conformations that are slowly interconverted to one another. Different conformations have been implicated in different mutagenic and repair outcomes. However, studies on the conformation-specific inhibition of replication, which is more relevant to cell survival, are scarce, presumably due to the structural dynamics of DNA lesions at the replication fork. It is difficult to capture the exact nature of replication inhibition by existing end-point assays, which usually detect either the ensemble of consequences of all the conformers or the culmination of all cellular behaviors, such as mutagenicity or survival rate. We previously reported very unusual sequence-dependent conformational heterogeneities involving FABP-modified DNA under different sequence contexts (TG₁*G₂T [67%B:33%S] and TG₁G₂*T [100%B], G*, N-(2′-deoxyguanosin-8-yl)-4′-fluoro-4-aminobiphenyl) (Cai et al. Nucleic Acids Research, 46, 6356–6370 (2018)). In the present study, we attempted to correlate the in vitro inhibition of polymerase activity to different conformations from a single FABP-modified DNA lesion. We utilized a combination of surface plasmon resonance (SPR) and HPLC-based steady-state kinetics to reveal the differences in terms of binding affinity and inhibition with polymerase between these two conformers (67%B:33%S and 100%B).

DNA sequence context plays a critical role in modulating the mutational effects of DNA damage. Here, we investigated how base identity influences the replication bypass and mutagenicity of a site-specific dG-AAF (2-acetylaminofluorene) bulky adduct in the well-defined AG*N and TG*N sequence contexts. By selecting A (purine) and T (pyrimidine) as representative 5’-flanking bases and systematically varying the 3’-base, we established a controlled system to examine sequence-dependent lesion replication. We found that the 5’-flanking base strongly affects the bypass profile, with AG*N sequences exhibiting uniformly low bypass (≤ 9.7%) and TG*N sequences showing markedly elevated bypass (23.6 – 50.4%) with strong sequence dependence. These differences may arise from the structure of the dG-AAF, whose conformation heterogeneities are sensitive to the flanking sequence context. In contrast, mutagenicity remains consistently low across all sequences examined, with a low frequency of point mutations and no detectable frameshift events. These results reveal a clear decoupling between lesion bypass efficiency and replication fidelity, where sequence context strongly controls lesion tolerance but has limited impact on mutagenicity. In total, our findings demonstrate that DNA sequence affects lesion processing, providing insights into how local sequence context shapes genome stability and mutational processes.

DNA sequence context plays a critical role in modulating the mutational effects of DNA damage. Here, we investigated how base identity influences the replication bypass and mutagenicity of a site-specific dG-AAF (2-acetylaminofluorene) bulky adduct in the well-defined AG*N and TG*N sequence contexts. By selecting adenine and thymine as 5′-flanking bases and systematically varying the 3′-base, we established a controlled system to examine sequence-dependent lesion replication. We found that the 5′-flanking base strongly affects the bypass profile, with AG*N sequences exhibiting uniformly low bypass (≤9.7%) and TG*N sequences showing markedly elevated bypass (23.6–50.4%) with strong sequence dependence. These differences may arise from the structure of the dG-AAF, whose conformation heterogeneities are sensitive to the flanking sequence context. In contrast, mutagenicity remains consistently low across all sequences examined, with a low frequency of point mutations and no detectable frameshift events. These results reveal a clear decoupling between lesion bypass efficiency and replication fidelity, where sequence context strongly controls lesion tolerance but has limited impact on mutagenicity. In total, our findings demonstrate that DNA sequence affects lesion processing, providing insights into how local sequence context shapes genome stability and mutational processes.