Proteomes

Background: Mitogen-activated protein kinase kinase kinase 3 (MAP3K3) is a serine/threonine kinase that exhibits oncogenic activity in various cancers. Despite the established role of MAP3K3 in signal transduction, its phosphosignaling landscape, including the mechanisms underlying its activation and the identification of its upstream kinases and downstream substrates, remains poorly characterized. Methods: To explore this network, we analyzed the global phosphoproteomics datasets to identify predominant sites of MAP3K3. Co-concordance and co-occurrence analyses were conducted to characterize the functional significance of site-specific phosphorylation of MAP3K3. Results: From the 588 profiling datasets and 124 differential datasets, we identified S340, S337, and S166 as predominant phosphosites. We then categorized the phosphosites in other proteins (PsOPs), which were positively and negatively co-concordant with the predominant sites of MAP3K3. From the known and predicted upstream kinases, substrates, and interactors, we isolated the PsOPs that have a role in carcinogenesis. Conclusions: Finally, by integrating these co-concordance data with the currently known and predicted upstream kinases, substrates, and interactors, we constructed a phosphosignaling network of MAP3K3-driven carcinogenesis. This network provides insights into the potential upstream kinases and substrates of MAP3K3 in the context of carcinogenesis.

Obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and dual-etiology metabolic dysfunction-associated alcohol-related liver disease (MetALD) form an overlapping metabolic dysfunction spectrum, rather than a single linear disease sequence. Proteomics offers a functional readout of this spectrum by measuring proteins, proteoforms, and protein species involved in tissue injury, inflammation, metabolic stress, and inter-organ communication. This review asks how proteomic data can support mechanism-based stratification, rather than simply generate disease-associated signatures. We summarize advances in circulating and tissue-based proteomics across obesity, T2D, MASLD/MASH, and MetALD, highlighting shared and disease-specific pathways such as mitochondrial dysfunction, extracellular matrix remodeling, immune activation, proteostasis stress, and endocrine crosstalk. We emphasize that proteomic clusters should be considered candidate endotypes only when they are reproducible, mechanistically coherent, linked to tissue or causal evidence, and clinically informative. We also evaluate bioinformatics and biostatistical strategies needed for reliable interpretation, including preprocessing, missing-data handling, normalization, longitudinal modeling, multi-omics integration, protein quantitative trait locus (pQTL) analysis, colocalization, and Mendelian randomization. Finally, we discuss how proteoforms, post-translational modifications (PTMs), and platform-dependent proteome complexity shape interpretation. Together, these concepts provide practical guidance for moving from proteomic signatures to candidate endotypes and for prioritizing clinically useful biomarkers and therapeutic targets.

Periodontal regeneration requires the reconstruction of root cementum, periodontal ligament, and alveolar bone, which are frequently disrupted by periodontitis, trauma, and other inflammatory conditions. Although periodontal ligament stem cells (PDLSCs) have been considered promising for periodontal tissue engineering because of their multipotency, self-renewal capacity, and immunomodulatory activity, direct cell-based therapy still faces various limitations, including donor variability, culture-related changes, delivery difficulties, and safety concerns. Exosomes and small extracellular vesicles derived from PDLSCs have therefore attracted attention as potential cell-free mediators of PDLSC paracrine activity. PDLSC-derived exosomes carry bioactive molecules, including proteins, lipids, messenger RNAs, and microRNAs, and can influence recipient cell behavior in periodontal and bone regenerative environments. In vitro and preclinical animal studies indicate that PDLSC-derived exosomes are involved in osteogenesis, periodontal attachment repair, cementogenesis, angiogenesis, mechanotransduction, cell proliferation/survival, and immune regulation. Their biological effects are closely related to the condition of their parental PDLSCs, their cargo, and the exosome isolation and characterization methods used. In this review, we summarize recent findings on the isolation strategies used, biological functions of, and therapeutic potential of PDLSC-derived exosomes, with particular focus on protein cargo, proteomic signatures, proteoform-related interpretation, and microRNA-mediated regulation. We also discuss current challenges in exosome isolation, characterization, delivery, stability, and reporting standards for future periodontal regenerative applications. The findings discussed throughout are preclinical, and their translation to clinical settings remains to be explored.